Publications by authors named "Yuan-Chin Lee"

86 Publications

Inhibition of Sp1-mediated survivin and MCL1 expression cooperates with SLC35F2 and myeloperoxidase to modulate YM155 cytotoxicity to human leukemia cells.

Biochem Pharmacol 2021 Apr 5;188:114544. Epub 2021 Apr 5.

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. Electronic address:

Although YM155 is reported to suppress survivin (also known as BIRC5) expression in cancer cells, its cytotoxic mechanism in human acute myeloid leukemia (AML) cells has not been clearly resolved. In this study, we analyzed the mechanistic pathways that modulate the sensitivity of human AML U937 and HL-60 cells to YM155. YM155 induced apoptosis in AML cells, which was characterized by p38 MAPK phosphorylation and downregulation of survivin and MCL1 expression. Phosphorylated p38 MAPK causes autophagy-mediated Sp1 degradation, thereby inhibiting the transcription of survivin and MCL1. The reduction of survivin and MCL1 levels further facilitated Sp1 protein degradation through autophagy. The restoration of Sp1, survivin, or MCL1 expression protected U937 and HL-60 cells from YM155-mediated cytotoxicity. U937 and HL-60 cells were continuously exposed to hydroquinone (HQ) to generate U937/HQ and HL-60/HQ cells, which showed increased SLC35F2 expression. The increase in SLC35F2 expression led to an increase in the sensitivity of U937/HQ cells to YM155-mediated cytotoxicity, whereas no such effect was observed in HL-60/HQ cells. Of note, myeloperoxidase (MPO) activity in HL-60 and HL-60/HQ cells enhanced YM155 cytotoxicity in these cells, and the enforced expression of MPO also increased the sensitivity of U937 cells to YM155. Taken together, we conclude that p38 MAPK-modulated autophagy inhibits Sp1-mediated survivin and MCL1 expression, which, in turn, leads to the death of U937 and HL-60 cells following YM155 treatment. In addition, our data indicate that SLC35F2 increases the sensitivity of U937 cells to YM155-mediated cytotoxicity, whereas MPO enhances YM155 cytotoxicity in U937 and HL-60 cells.
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http://dx.doi.org/10.1016/j.bcp.2021.114544DOI Listing
April 2021

Modification of carboxyl groups converts α-lactalbumin into an active molten globule state with membrane-perturbing activity and cytotoxicity.

Int J Biol Macromol 2020 Nov 19;163:1697-1706. Epub 2020 Sep 19.

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. Electronic address:

We investigated whether the modification of the negatively charged carboxyl groups with semicarbazide could confer membrane-disrupting and cytotoxic properties to bovine α-lactalbumin (LA). MALDI-TOF analysis revealed that eighteen of the twenty-one carboxyl groups in LA were coupled with semicarbazide molecules. Measurement of circular dichroism spectra and Trp fluorescence quenching studies showed that semicarbazide-modified LA (SEM-LA) had a molten globule-like conformation that retained the α-helix secondary structure but lost the tertiary structure of LA. Compared to LA, SEM-LA had a higher structural flexibility in response to trifluoroethanol- and temperature-induced structural transitions. In sharp contrast to LA, SEM-LA exhibited membrane-damaging activity and cytotoxicity. Furthermore, SEM-LA-induced membrane permeability promoted the uptake of daunorubicin and thereby its cytotoxicity. The microenvironment surrounding the Trp residues of SEM-LA was enriched in positive charges, as revealed by iodide quenching studies. The binding of SEM-LA with lipid vesicles altered the positively charged cluster around Trp residues. Although LA and SEM-LA displayed similar lipid-binding affinities, the membrane interaction modes of SEM-LA and LA differed. Collectively, these results suggest that blocking of negatively charged residues enables the formation of a molten-globule conformation of LA with structural flexibility and increased positive charge, thereby generating functional LA with membrane-disrupting activity and cytotoxicity.
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http://dx.doi.org/10.1016/j.ijbiomac.2020.09.095DOI Listing
November 2020

Blocking of negative charged carboxyl groups converts Naja atra neurotoxin to cardiotoxin-like protein.

Int J Biol Macromol 2020 Dec 23;164:2953-2963. Epub 2020 Aug 23.

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. Electronic address:

Naja atra cobrotoxin and cardiotoxin 3 (CTX3) exhibit neurotoxicity and cytotoxicity, respectively. In the present study, we aimed to investigate whether the carboxyl groups of cobrotoxin play a role in structural constraints, thereby preventing cobrotoxin from exhibiting cytotoxic activity. Six of the seven carboxyl groups in cobrotoxin were conjugated with semicarbazide. Measurement of circular dichroism spectra and Trp fluorescence quenching showed that the gross conformation of semicarbazide-modified cobrotoxin (SEM-cobrotoxin) and cobrotoxin differed. In sharp contrast to cobrotoxin, SEM-cobrotoxin demonstrated membrane-damaging activity and cytotoxicity, which are feature more characteristic of CTX3. Furthermore, both SEM-cobrotoxin and CTX3 induced cell death through AMPK activation. Analyses of the interaction between polydiacetylene/lipid vesicles and fluorescence-labeled lipids revealed that SEM-cobrotoxin and cobrotoxin adopted different membrane-bound states. The structural characteristics of SEM-cobrotoxin were similar to those of CTX3, including trifluoroethanol (TFE)-induced structural transformation and membrane binding-induced conformational change. Conversely, cobrotoxin was insensitive to the TFE-induced effect. Collectively, the data of this study indicate that blocking negatively charged residues confers cobrotoxin with membrane-damaging activity and cytotoxicity. The findings also suggest that the structural constraints imposed by carboxyl groups control the functional properties of snake venom α-neurotoxins during the divergent evolution of snake venom neurotoxins and cardiotoxins.
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http://dx.doi.org/10.1016/j.ijbiomac.2020.08.163DOI Listing
December 2020

GSK3β suppression inhibits MCL1 protein synthesis in human acute myeloid leukemia cells.

J Cell Physiol 2021 Jan 22;236(1):570-586. Epub 2020 Jun 22.

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.

Previous studies have shown that glycogen synthase kinase 3β (GSK3β) suppression is a potential strategy for human acute myeloid leukemia (AML) therapy. However, the cytotoxic mechanism associated with GSK3β suppression remains unresolved. Thus, the underlying mechanism of N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea (AR-A014418)-elicited GSK3β suppression in the induction of AML U937 and HL-60 cell death was investigated in this study. Our study revealed that AR-A014418-induced MCL1 downregulation remarkably elicited apoptosis of U937 cells. Furthermore, the AR-A014418 treatment increased p38 MAPK phosphorylation and decreased the phosphorylated Akt and ERK levels. Activation of p38 MAPK subsequently evoked autophagic degradation of 4EBP1, while Akt inactivation suppressed mTOR-mediated 4EBP1 phosphorylation. Furthermore, AR-A014418-elicited ERK inactivation inhibited Mnk1-mediated eIF4E phosphorylation, which inhibited MCL1 mRNA translation in U937 cells. In contrast to GSK3α, GSK3β downregulation recapitulated the effect of AR-A014418 in U937 cells. Transfection of constitutively active GSK3β or cotransfection of constitutively activated MEK1 and Akt suppressed AR-A014418-induced MCL1 downregulation. Moreover, AR-A014418 sensitized U937 cells to ABT-263 (BCL2/BCL2L1 inhibitor) cytotoxicity owing to MCL1 suppression. Collectively, these results indicate that AR-A014418-induced GSK3β suppression inhibits ERK-Mnk1-eIF4E axis-modulated de novo MCL1 protein synthesis and thereby results in U937 cell apoptosis. Our findings also indicate a similar pathway underlying AR-A014418-induced death in human AML HL-60 cells.
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http://dx.doi.org/10.1002/jcp.29884DOI Listing
January 2021

Lessons learned from the INHANCE consortium: An overview of recent results on head and neck cancer.

Oral Dis 2021 Jan 16;27(1):73-93. Epub 2020 Jul 16.

Branch of Medical Statistics, Biometry, and Epidemiology "G. A. Maccacaro", Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy.

Objective: To summarize the latest evidence on head and neck cancer epidemiology from the International Head and Neck Cancer Epidemiology (INHANCE) consortium.

Subjects And Methods: INHANCE was established in 2004 to elucidate the etiology of head and neck cancer through pooled analyses of individual-level data on a large scale. We summarize results from recent INHANCE-based publications updating our 2015 overview.

Results: Seventeen papers were published between 2015 and May 2020. These studies further define the nature of risks associated with tobacco and alcohol, and occupational exposures on head and neck cancer. The beneficial effects on incidence of head and neck cancer were identified for good oral health, endogenous and exogenous hormonal factors, and selected aspects of diet related to fruit and vegetables. INHANCE has begun to develop risk prediction models and to pool follow-up data on their studies, finding that ~30% of cases had cancer recurrence and 9% second primary cancers, with overall- and disease-specific 5-year-survival of 51% and 57%, respectively.

Conclusions: The number and importance of INHANCE scientific findings provides further evidence of the advantages of large-scale internationally collaborative projects and will support the development of prevention strategies.
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http://dx.doi.org/10.1111/odi.13502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752834PMC
January 2021

Albendazole-Induced SIRT3 Upregulation Protects Human Leukemia K562 Cells from the Cytotoxicity of MCL1 Suppression.

Int J Mol Sci 2020 May 30;21(11). Epub 2020 May 30.

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.

Previous studies have shown that MCL1 stabilization confers cancer cells resistance to microtubule targeting agents (MTAs) and functionally extends the lifespan of MTA-triggered mitotically arrested cells. Albendazole (ABZ), a benzimidazole anthelmintic, shows microtubule-destabilizing activity and has been repositioned for cancer therapies. To clarify the role of MCL1 in ABZ-induced apoptosis, we investigated the cytotoxicity of ABZ on human leukemia K562 cells. Treatment with ABZ for 24 h did not appreciably induce apoptosis or mitochondrial depolarization in K562 cells, though it caused the mitotic arrest of K562 cells. ABZ-evoked p38 MAPK activation concurrently suppressed Sp1-mediated MCL1 expression and increased SIRT3 mRNA stability and protein expression. ABZ and A-1210477 (an MCL1 inhibitor) enhanced the cytotoxicity of ABT-263 (a BCL2/BCL2L1 inhibitor) to their effect on MCL1 suppression. Unlike ABZ, A-1210477 did not affect SIRT3 expression and reduced the survival of K562 cells. Overexpression of SIRT3 attenuated the A-1210477 cytotoxicity on K562 cells. ABZ treatment elicited marked apoptosis and ΔΨm loss in ABT-263-resistant K562 (K562/R) cells, but did not alter SIRT3 expression. Ectopic expression of SIRT3 alleviated the cytotoxicity of ABZ on K562/R cells. Collectively, our data demonstrate that ABZ-induced SIRT3 upregulation delays the apoptosis-inducing effect of MCL1 suppression on apoptosis induction in K562 cells.
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http://dx.doi.org/10.3390/ijms21113907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312678PMC
May 2020

Inhibition of EGFR pathway promotes the cytotoxicity of ABT-263 in human leukemia K562 cells by blocking MCL1 upregulation.

Biochem Pharmacol 2020 08 22;178:114047. Epub 2020 May 22.

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. Electronic address:

ABT-263 induces MCL1 upregulation in cancer cells, which confers resistance to the drug. An increased understanding of the mechanism underlying ABT-263-induced MCL1 expression may provide a strategy to improve its tumor-suppression activity. The present study revealed that ABT-263 reduced the turnover of MCL1 mRNA, thereby upregulating MCL1 expression in human K562 leukemia cells. Furthermore, ABT-263-induced EGFR activation promoted AGO2 phosphorylation at Y393 and reduced miR-125b maturation. Treatment with EGFR inhibitors mitigated MCL1 upregulation induced by ABT-263. Additionally, lithium chloride (LiCl) alleviated ABT-263-induced MCL1 upregulation through EGFR-AGO2 axis-modulated miR-125b suppression. Ectopic expression of dominant negative AGO2(Y393F) or transfection with miR-125b abolished ABT-263-induced upregulation of MCL1 mRNA and protein levels. Co-treatment with either EGFR inhibitors or LiCl collaboratively enhanced ABT-263 cytotoxicity, while MCL1 overexpression eliminated this synergistic effect. Collectively, our data reveal that ABT-263 increases EGFR-mediated AGO2 phosphorylation, which in turn suppresses miR-125b-mediated MCL1 mRNA degradation in K562 cells. The suppression of this signaling pathway results in the synergistic cytotoxic effect of EGFR inhibitors or LiCl and ABT-263.
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http://dx.doi.org/10.1016/j.bcp.2020.114047DOI Listing
August 2020

Status of Asp29 and Asp40 in the Interaction of Cardiotoxins with Lipid Bilayers.

Toxins (Basel) 2020 04 18;12(4). Epub 2020 Apr 18.

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.

It is widely accepted that snake venom cardiotoxins (CTXs) target the plasma membranes of cells. In the present study, we investigated the role of Asp residues in the interaction of cardiotoxin 1 (CTX1) and cardiotoxin 3 (CTX3) with phospholipid bilayers using chemical modification. CTX1 contains three Asp residues at positions 29, 40, and 57; CTX3 contains two Asp residues at positions 40 and 57. Compared to Asp29 and Asp40, Asp57 was sparingly modified with semi-carbazide, as revealed by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass and mass/mass analyses. Thus, semi-carbazide-modified CTX1 (SEM-CTX1) mainly contained modified Asp29 and Asp40, while SEM-CTX3 contained modified Asp40. Compared to that of native toxins, trifluoroethanol easily induced structural transition of SEM-CTX1 and SEM-CTX3, suggesting that the structural flexibility of CTXs was constrained by Asp40. Modification of Asp29 and Asp40 markedly promoted the ability of CTX1 to induce permeability of cell membranes and lipid vesicles; CTX3 and SEM-CTX3 showed similar membrane-damaging activity. Modification of Asp residues did not affect the membrane-binding capability of CTXs. Circular dichroism spectra of SEM-CTX3 and CTX3 were similar, while the gross conformation of SEM-CTX1 was distinct from that of CTX1. The interaction of CTX1 with membrane was distinctly changed by Asp modification. Collectively, our data suggest that Asp29 of CTX1 suppresses the optimization of membrane-bound conformation to a fully active state and that the function of Asp40 in the structural constraints of CTX1 and CTX3 is not important for the manifestation of membrane-perturbing activity.
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http://dx.doi.org/10.3390/toxins12040262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232319PMC
April 2020

Arsenic trioxide-induced p38 MAPK and Akt mediated MCL1 downregulation causes apoptosis of BCR-ABL1-positive leukemia cells.

Toxicol Appl Pharmacol 2020 Apr 17;397:115013. Epub 2020 Apr 17.

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. Electronic address:

In this study, we investigated the mechanisms underlying arsenic trioxide (ATO)-induced death of human BCR-ABL1-positive K562 and MEG-01 cells. ATO-induced apoptotic death in K562 cells was characterized by ROS-mediated mitochondrial depolarization, MCL1 downregulation, p38 MAPK activation, and Akt inactivation. ATO-induced BCR-ABL1 downregulation caused Akt inactivation but not p38 MAPK activation. Akt inactivation increased GSK3β-mediated MCL1 degradation, while p38 MAPK-mediated NFκB activation coordinated with HDAC1 suppressed MCL1 transcription. Inhibition of p38 MAPK activation or overexpression of constitutively active Akt increased MCL1 expression and promoted the survival of ATO-treated cells. Overexpression of MCL1 alleviated mitochondrial depolarization and cell death induced by ATO. The same pathway was found to be involved in ATO-induced death in MEG-01 cells. Remarkably, YM155 synergistically enhanced the cytotoxicity of ATO on K562 and MEG-01 cells through suppression of MCL1 and survivin. Collectively, our data indicate that ATO-induced p38 MAPK- and Akt-mediated MCL1 downregulation triggers apoptosis in K562 and MEG-01 cells, and that p38 MAPK activation is independent of ATO-induced BCR-ABL1 suppression.
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http://dx.doi.org/10.1016/j.taap.2020.115013DOI Listing
April 2020

SIRT3, PP2A and TTP protein stability in the presence of TNF-α on vincristine-induced apoptosis of leukaemia cells.

J Cell Mol Med 2020 02 13;24(4):2552-2565. Epub 2020 Jan 13.

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.

The contribution of vincristine (VCR)-induced microtubule destabilization to evoke apoptosis in cancer cells remains to be resolved. Thus, we investigated the cytotoxic mechanism of VCR on U937 and HL-60 human leukaemia cell lines. We discovered that VCR treatment resulted in the up-regulation of TNF-α expression and activation of the death receptor pathway, which evoked apoptosis of U937 cells. Moreover, VCR induced microtubule destabilization and mitotic arrest. VCR treatment down-regulated SIRT3, and such down-regulation caused mitochondrial ROS to initiate phosphorylation of p38 MAPK. p38 MAPK suppressed MID1-modulated degradation of the protein phosphatase 2A (PP2A) catalytic subunit. The SIRT3-ROS-p38 MAPK-PP2A axis inhibited tristetraprolin (TTP)-controlled TNF-α mRNA degradation, consequently, up-regulating TNF-α expression. Restoration of SIRT3 and TTP expression, or inhibition of the ROS-p38 MAPK axis increased the survival of VCR-treated cells and repressed TNF-α up-regulation. In contrast to suppression of the ROS-p38 MAPK axis, overexpression of SIRT3 modestly inhibited the effect of VCR on microtubule destabilization and mitotic arrest in U937 cells. Apoptosis of HL-60 cells, similarly, went through the same pathway. Collectively, our data indicate that the SIRT3-ROS-p38 MAPK-PP2A-TTP axis modulates TNF-α expression, which triggers apoptosis of VCR-treated U937 and HL-60 cells. We also demonstrate that the apoptotic signalling is not affected by VCR-elicited microtubule destabilization.
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http://dx.doi.org/10.1111/jcmm.14949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028858PMC
February 2020

Dietary glycaemic index, glycaemic load and head and neck cancer risk: a pooled analysis in an international consortium.

Br J Cancer 2020 03 13;122(6):745-748. Epub 2020 Jan 13.

Department of Clinical Sciences and Community Health, Università degli Studi di Milano, via Venezian, 1, 20133, Milano, Italy.

High dietary glycaemic index (GI) and glycaemic load (GL) may increase cancer risk. However, limited information was available on GI and/or GL and head and neck cancer (HNC) risk. We conducted a pooled analysis on 8 case-control studies (4081 HNC cases; 7407 controls) from the International Head and Neck Cancer Epidemiology (INHANCE) consortium. We estimated the odds ratios (ORs) and 95% confidence intervals (CIs) of HNC, and its subsites, from fixed- or mixed-effects logistic models including centre-specific quartiles of GI or GL. GI, but not GL, had a weak positive association with HNC (OR = 1.16; 95% CI = 1.02-1.31). In subsites, we found a positive association between GI and laryngeal cancer (OR = 1.60; 95% CI = 1.30-1.96) and an inverse association between GL and oropharyngeal cancer (OR = 0.78; 95% CI = 0.63-0.97). This pooled analysis indicates a modest positive association between GI and HNC, mainly driven by laryngeal cancer.
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http://dx.doi.org/10.1038/s41416-019-0702-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078183PMC
March 2020

Compound C induces autophagy and apoptosis in parental and hydroquinone-selected malignant leukemia cells through the ROS/p38 MAPK/AMPK/TET2/FOXP3 axis.

Cell Biol Toxicol 2020 08 3;36(4):315-331. Epub 2020 Jan 3.

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan.

Hydroquinone (HQ), a major metabolic product of benzene, causes acute myeloid leukemia (AML) elicited by benzene exposure. Past studies found that continuous exposure of human AML U937 cells to HQ selectively produces malignant U937/HQ cells in which FOXP3 upregulation modulates malignant progression. Other studies revealed that AMPK promotes TET2 activity on DNA demethylation and that TET2 activity is crucial for upregulating FOXP3 expression. This study was conducted to elucidate whether compound C, an AMPK inhibitor, blocked the AMPK-TET2-FOXP3 axis in AML and in HQ-selected malignant cells. We found higher levels of AMPKα, TET2, and FOXP3 expression in U937/HQ cells compared to U937 cells. Treatment of parental Original Article and HQ-selected malignant U937 cells with compound C induced ROS-mediated p38 MAPK activation, leading to a suppression of AMPKα, TET2, and FOXP3 expression. Moreover, compound C induced apoptosis and mTOR-independent autophagy. The suppression of the autophagic flux inhibited the apoptosis of compound C-treated U937 and U937/HQ cells, whereas co-treatment with rapamycin, a mTOR inhibitor, sensitized the two cell lines to compound C cytotoxicity. Overexpression of AMPKα1 or pretreatment with autophagic inhibitors abrogated compound C-induced autophagy and suppression of TET2 and FOXP3 expression. Restoration of AMPKα1 or FOXP3 expression increased cell survival after treatment with compound C. In conclusion, our results show that compound C suppresses AMPK/TET2 axis-mediated FOXP3 expression and induces autophagy-dependent apoptosis in parental and HQ-selected malignant U937 cells, suggesting that the AMPK/TET2/FOXP3 axis is a promising target for improving AML therapy and attenuating benzene exposure-induced AML progression.
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http://dx.doi.org/10.1007/s10565-019-09495-3DOI Listing
August 2020

Autophagic HuR mRNA degradation induces survivin and MCL1 downregulation in YM155-treated human leukemia cells.

Toxicol Appl Pharmacol 2020 01 16;387:114857. Epub 2019 Dec 16.

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. Electronic address:

The aim of this study was to investigate the mechanism of YM155 cytotoxicity in human chronic myeloid leukemia (CML) cells. YM155-induced apoptosis of human CML K562 cells was characterized by ROS-mediated p38 MAPK activation, mitochondrial depolarization, and survivin and MCL1 downregulation. Moreover, YM155-induced autophagy caused degradation of HuR mRNA and downregulation of HuR protein expression, which resulted in destabilized survivin and MCL1 mRNA. Interestingly, survivin and MCL1 suppression contributed to autophagy-mediated HuR mRNA destabilization in YM155-treated cells. Pretreatment with inhibitors of p38 MAPK or autophagy alleviated YM155-induced autophagy and apoptosis in K562 cells, as well as YM155-induced downregulation of HuR, survivin, and MCL1. Ectopic overexpression of HuR, survivin, or MCL1 attenuated the cytotoxic effect of YM155 on K562 cells. Conversely, YM155 sensitized K562 cells to ABT-199 (a BCL2 inhibitor), and circumvented K562 cell resistance to ABT-199 because of its inhibitory effect on survivin and MCL1 expression. Overall, our data indicate that YM155-induced apoptosis is mediated by inducing autophagic HuR mRNA degradation, and reveal the pathway responsible for YM155-induced downregulation of survivin and MCL1 in K562 cells. Our findings also indicate a similar pathway underlying YM155-induced death in human CML MEG-01 cells.
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http://dx.doi.org/10.1016/j.taap.2019.114857DOI Listing
January 2020

Tobacco smoking, chewing habits, alcohol drinking and the risk of head and neck cancer in Nepal.

Int J Cancer 2020 08 27;147(3):866-875. Epub 2019 Dec 27.

Division of Public Health, Department of Family & Preventive Medicine, University of Utah School of Medicine, and Huntsman Cancer Institute, Salt Lake City, UT.

Although tobacco smoking, pan chewing and alcohol drinking are important risk factors for head and neck cancer (HNC), the HNC risks conferred by products available in Nepal for these habits are unknown. We assessed the associations of tobacco smoking, chewing habits, and alcohol drinking with HNC risk in Nepal. A case-control study was conducted in Nepal with 549 incident HNC cases and 601 controls. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression adjusting for potential confounders. We observed increased HNC risk for tobacco smoking (OR: 1.54; 95% CI: 1.14, 2.06), chewing habits (OR: 2.39; 95% CI: 1.77, 3.23), and alcohol drinking (OR: 1.57; 95% CI: 1.14, 2.18). The population attributable fraction (PAF) was 24.3% for tobacco smoking, 39.9% for chewing habits and 23.0% for alcohol drinking. Tobacco smoking, chewing habits, and alcohol drinking might be responsible for 85.3% of HNC cases. Individuals who smoked tobacco, chewed products and drank alcohol had a 13-fold increase in HNC risk (OR: 12.83; 95% CI: 6.91, 23.81) compared to individuals who did not have any of these habits. Both high frequency and long duration of these habits were strong risk factors for HNC among the Nepalese with clear dose-response trends. Preventive strategies against starting these habits and support for quitting these habits are necessary to decrease the incidence of HNC in Nepal.
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http://dx.doi.org/10.1002/ijc.32823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906484PMC
August 2020

Risk Prediction Models for Head and Neck Cancer in the US Population From the INHANCE Consortium.

Am J Epidemiol 2020 04;189(4):330-342

Head and neck cancer (HNC) risk prediction models based on risk factor profiles have not yet been developed. We took advantage of the large database of the International Head and Neck Cancer Epidemiology (INHANCE) Consortium, including 14 US studies from 1981-2010, to develop HNC risk prediction models. Seventy percent of the data were used to develop the risk prediction models; the remaining 30% were used to validate the models. We used competing-risk models to calculate absolute risks. The predictors included age, sex, education, race/ethnicity, alcohol drinking intensity, cigarette smoking duration and intensity, and/or family history of HNC. The 20-year absolute risk of HNC was 7.61% for a 60-year-old woman who smoked more than 20 cigarettes per day for over 20 years, consumed 3 or more alcoholic drinks per day, was a high school graduate, had a family history of HNC, and was non-Hispanic white. The 20-year risk for men with a similar profile was 6.85%. The absolute risks of oropharyngeal and hypopharyngeal cancers were generally lower than those of oral cavity and laryngeal cancers. Statistics for the area under the receiver operating characteristic curve (AUC) were 0.70 or higher, except for oropharyngeal cancer in men. This HNC risk prediction model may be useful in promoting healthier behaviors such as smoking cessation or in aiding persons with a family history of HNC to evaluate their risks.
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http://dx.doi.org/10.1093/aje/kwz259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274188PMC
April 2020

Age at start of using tobacco on the risk of head and neck cancer: Pooled analysis in the International Head and Neck Cancer Epidemiology Consortium (INHANCE).

Cancer Epidemiol 2019 12 3;63:101615. Epub 2019 Oct 3.

Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.

Background: Tobacco use is a well-established risk factor for head and neck cancer (HNC). However, less is known about the potential impact of exposure to tobacco at an early age on HNC risk.

Methods: We analyzed individual-level data on ever tobacco smokers from 27 case-control studies (17,146 HNC cases and 17,449 controls) in the International Head and Neck Cancer Epidemiology (INHANCE) consortium. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using random-effects logistic regression models.

Results: Without adjusting for tobacco packyears, we observed that younger age at starting tobacco use was associated with an increased HNC risk for ever smokers (OR: 1.64, 95% CI: 1.35, 1.97). However, the observed association between age at starting tobacco use and HNC risk became null after adjusting for tobacco packyears (OR: 0.97, 95% CI: 0.80, 1.19). In the stratified analyses on HNC subsites by tobacco packyears or years since quitting, no difference in the association between age at start and HNC risk was observed.

Conclusions: Results from this pooled analysis suggest that increased HNC risks observed with earlier age at starting tobacco smoking are largely due to longer duration and higher cumulative tobacco exposures.
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http://dx.doi.org/10.1016/j.canep.2019.101615DOI Listing
December 2019

Cardiotoxin 3 Elicits Autophagy and Apoptosis in U937 Human Leukemia Cells through the Ca/PP2A/AMPK Axis.

Toxins (Basel) 2019 09 12;11(9). Epub 2019 Sep 12.

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.

Cardiotoxins (CTXs) are suggested to exert their cytotoxicity through cell membrane damage. Other studies show that penetration of CTXs into cells elicits mitochondrial fragmentation or lysosome disruption, leading to cell death. Considering the role of AMPK-activated protein kinase (AMPK) in mitochondrial biogenesis and lysosomal biogenesis, we aimed to investigate whether the AMPK-mediated pathway modulated (Taiwan cobra) CTX3 cytotoxicity in U937 human leukemia cells. Our results showed that CTX3 induced autophagy and apoptosis in U937 cells, whereas autophagic inhibitors suppressed CTX3-induced apoptosis. CTX3 treatment elicited Ca-dependent degradation of the protein phosphatase 2A (PP2A) catalytic subunit (PP2Acα) and phosphorylation of AMPKα. Overexpression of PP2Acα mitigated the CTX3-induced AMPKα phosphorylation. CTX3-induced autophagy was via AMPK-mediated suppression of the Akt/mTOR pathway. Removal of Ca or suppression of AMPKα phosphorylation inhibited the CTX3-induced cell death. CTX3 was unable to induce autophagy and apoptosis in U937 cells expressing constitutively active Akt. Met-modified CTX3 retained its membrane-perturbing activity, however, it did not induce AMPK activation and death of U937 cells. These results conclusively indicate that CTX3 induces autophagy and apoptosis in U937 cells via the Ca/PP2A/AMPK axis, and suggest that the membrane-perturbing activity of CTX3 is not crucial for the cell death signaling pathway induction.
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http://dx.doi.org/10.3390/toxins11090527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784133PMC
September 2019

Occupations and the Risk of Head and Neck Cancer: A Pooled Analysis of the International Head and Neck Cancer Epidemiology (INHANCE) Consortium.

J Occup Environ Med 2019 05;61(5):397-404

The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City, New York (Dr Khetan, Dr Boffetta, Dr Hashim); University of Rennes, National Institute of Health and Medical Research, School of Advanced Studies in Public Health, Institute for Health, Environment and Work Research - Research Unit UMR_S 1085, Pointe-à-Pitre, France (Dr Luce); Cancer and Environment Team, National Institute of Health and Medical Research U1018, Paris-Sud University, Paris-Saclay University, Villejuif, France (Dr Stucker); Cancer and Environment team (CESP), (Inserm) National Institute of Health and Medical Research U1018, Paris-Sud University, Paris-Saclay University, Villejuif, France (Dr Stucker); Federal University of Pelotas, Pelotas (Dr Menezes); University of Sao Paulo, Sao Paulo, Brazil (Dr Wunsch-Filho); Leibniz Institute for Prevention Research and Epidemiology, Bremen Institute for Prevention Research and Social Medicine , Bremen, Germany (Dr Ahrens); School of Medicine, National and Kapodistrian University of Athens, Greece (Dr Lagiou); Oncological Reference Center, Institute of Scientific Characterization and Hospitalization, Aviano, Italy (Dr Serraino); Department of Medical Sciences, University of Turin, Turin (Dr Richiardi); Cancer Registry of Norway, Institute of Population-based Cancer Research, Oslo, Norway (Dr Kjaerheim); School of Medicine, Dentistry, and Nursing, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK (Dr Conway); University of Hong Kong, Hong Kong, China (Dr Thomson); Penn State College of Medicine, Hershey, Pennsylvania (Dr Muscat); National Institute of Public Health, Bucharest, Romania (Dr Mates); University of Heidelberg (Dr Ramroth); National Institute of Health and Medical Research, Sorbonne University, Pierre Louis Institute of Epidemiology and Public Health, Paris, France (Dr Menvielle); Fred Hutchinson Cancer Research Center, Seattle, Washington (Dr Vaughan); Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany (Dr Brenner); Division of Preventive Oncology, German Cancer Research Center and National Center for Tumor Diseases, Heidelberg, Germany (Dr Brenner); German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany Hermann Brenner (Dr Brenner); Division of Public Health, Department of Family & Preventive Medicine and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah (Dr Lee, Dr Hashibe); Department of Clinical Sciences and Community Health, University of Milan, Milan (Dr La Vecchia), Italy.

Objective: To investigate the associations between head and neck cancer (HNC) risk and occupations.

Methods: We harmonized data on occupations in a pooled analysis of 8839 HNC cases and 13,730 controls in International Head and Neck Cancer Epidemiology (INHANCE) consortium. Logistic regression was used to estimate odds ratios (ORs) for associations of occupations and HNC risk. Population attributable fraction (PAF) for occupations was calculated using the formula PEC × (OR - 1)/OR.

Results: Trend of increasing HNC risk was found with increasing duration of employment for many occupations, including cooks (OR = 1.36; 95% confidence interval [CI] 1.09 to 1.68), cleaners (OR = 1.38; 95% CI 1.13 to 1.69), painters (OR = 1.82; 95% CI 1.42 to 2.35). The PAF for a priori occupations was 14.5% (95% CI 7.1% to 21.9%) for HNC.

Conclusions: We found associations between certain occupations and HNC risks, including for subsites, with a duration-response relationship.
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http://dx.doi.org/10.1097/JOM.0000000000001563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613803PMC
May 2019

Naja atra cardiotoxins enhance the protease activity of chymotrypsin.

Int J Biol Macromol 2019 Sep 12;136:512-520. Epub 2019 Jun 12.

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. Electronic address:

Snake venom cardiotoxins (CTXs) present diverse pharmacological functions. Previous studies have reported that CTXs affect the activity of some serine proteases, namely, chymotrypsin, subtilisin, trypsin, and acetylcholinesterase. To elucidate the mode of action of CTXs, the interaction of CTXs with chymotrypsin was thus investigated. It was found that Naja atra CTX isotoxins concentration-dependently enhanced chymotrypsin activity. The capability of CTX1 and CTX5 in increasing chymotrypsin activity was higher than that of CTX2, CTX3, and CTX4. Removal of the molecular beacon-bound CTXs by chymotrypsin, circular dichroism measurement, and acrylamide quenching of Trp fluorescence indicated that CTXs bound to chymotrypsin. Chemical modification of Lys, Arg, or Met residues of CTX1 attenuated its capability to enhance chymotrypsin activity without impairing their bond with chymotrypsin. Catalytically inactive chymotrypsin retained the binding affinity for native and modified CTX1. CTX1 and chemically modified CTX1 differently altered the global conformation of chymotrypsin and inactivated chymotrypsin. Moreover, CTX1 did not reduce the interaction of 2-(p-toluidino)-naphthalene-6-sulfonate (TNS) with chymotrypsin and inactivated chymotrypsin. Together with previous results revealing that TNS can bind at the hydrophobic region of active site in chymotrypsin, our data suggest that CTXs can enhance chymotrypsin activity by binding to the region outside the enzyme's active site.
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http://dx.doi.org/10.1016/j.ijbiomac.2019.06.066DOI Listing
September 2019

Joint effects of intensity and duration of cigarette smoking on the risk of head and neck cancer: A bivariate spline model approach.

Oral Oncol 2019 07 17;94:47-57. Epub 2019 May 17.

International Agency for Research on Cancer, Lyon, France.

Objectives: This study aimed at re-evaluating the strength and shape of the dose-response relationship between the combined (or joint) effect of intensity and duration of cigarette smoking and the risk of head and neck cancer (HNC). We explored this issue considering bivariate spline models, where smoking intensity and duration were treated as interacting continuous exposures.

Materials And Methods: We pooled individual-level data from 33 case-control studies (18,260 HNC cases and 29,844 controls) participating in the International Head and Neck Cancer Epidemiology (INHANCE) consortium. In bivariate regression spline models, exposures to cigarette smoking intensity and duration (compared with never smokers) were modeled as a linear piecewise function within a logistic regression also including potential confounders. We jointly estimated the optimal knot locations and regression parameters within the Bayesian framework.

Results: For oral-cavity/pharyngeal (OCP) cancers, an odds ratio (OR) >5 was reached after 30 years in current smokers of ∼20 or more cigarettes/day. Patterns of OCP cancer risk in current smokers differed across strata of alcohol intensity. For laryngeal cancer, ORs >20 were found for current smokers of ≥20 cigarettes/day for ≥30  years. In former smokers who quit ≥10  years ago, the ORs were approximately halved for OCP cancers, and ∼1/3 for laryngeal cancer, as compared to the same levels of intensity and duration in current smokers.

Conclusion: Referring to bivariate spline models, this study better quantified the joint effect of intensity and duration of cigarette smoking on HNC risk, further stressing the need of smoking cessation policies.
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http://dx.doi.org/10.1016/j.oraloncology.2019.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7117823PMC
July 2019

Body mass index and the risk of head and neck cancer in the Chinese population.

Cancer Epidemiol 2019 06 7;60:208-215. Epub 2019 May 7.

Division of Public Health, Department of Family and Preventive Medicine, University of Utah School of Medicine and Huntsman Cancer Institute, Salt Lake City, UT, USA. Electronic address:

Objective: To investigate potential associations between body mass index (BMI) and head and neck cancer (HNC) risk in an East Asian population.

Methods: We conducted a hospital-based multicenter case-control study in East Asia including 921 cases and 806 controls. We estimated the odds ratios (ORs) and 95% confidence intervals (95% CI) for HNC risks by using logistic regression, adjusting on potential confounders.

Results: Compared to normal BMI at interview (18.5-<25 kg/m), being underweight (BMI < 18.5 kg/m) was associated with a higher HNC risk (OR = 2.71, 95% CI  1.40-5.26). Additionally, obesity (BMI > 30 kg/m) was associated with a lower HNC risk (OR = 0.30, 95% CI  0.16-0.57). Being underweight at age 20 was also associated with an increased risk of HNC. However, being underweight at 5 years or 2 years before interview was not associated with a higher risk of HNC.

Conclusion: We observed an inverse association between BMI and HNC risk, which is consistent with previous studies in other geographic regions. Being underweight at age 20 was also associated with a higher risk of HNC, suggesting that reverse causality was not the main source of the association.
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http://dx.doi.org/10.1016/j.canep.2019.04.008DOI Listing
June 2019

Involuntary smoking and the risk of head and neck cancer in an East Asian population.

Cancer Epidemiol 2019 04 19;59:173-177. Epub 2019 Feb 19.

Division of Public Health, Department of Family and Preventive Medicine, University of Utah School of Medicine, and Huntsman Cancer Institute, Salt Lake City, UT, United States.

Background: Although tobacco involuntary smoking is an established risk factor for lung cancer, the association with head and neck cancer (HNC) is not established. We aimed to investigate this potential association in an East Asian population.

Methods: We conducted a multicenter case-control study in East Asia including eight centers. We restricted our analysis to never tobacco smokers (303 cases and 459 controls) and to never tobacco smokers/never alcohol drinkers (243 cases and 403 controls).

Results: Among never tobacco smokers, involuntary smoking was associated with a 1.47-fold increase in risk of HNC (95%CI = 1.02, 2.13) and a 1.8-fold increase in the risk of oral cavity cancer (95%CI = 1.14, 2.92). Among never tobacco smokers who were also never alcohol drinkers, increased risks were detected for more than 3 h per day of involuntary smoking exposure and for 15 or more years of exposure. A dose-response relation was suggested for frequency of exposure (p for trend = 0.014) and for years of exposure (p for trend = 0.010) for oral cavity cancer. We did not detect strong increases in the risk of the other HNC subsites.

Conclusions: Our study supports the association between involuntary smoking and the risk of HNC. The association may be stronger for oral cavity cancer than for other HNC subsites.
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http://dx.doi.org/10.1016/j.canep.2019.01.020DOI Listing
April 2019

Fiber intake and the risk of head and neck cancer in the prostate, lung, colorectal and ovarian (PLCO) cohort.

Int J Cancer 2019 11 12;145(9):2342-2348. Epub 2019 Feb 12.

Division of Public Health, Department of Family and Preventive Medicine, and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT.

Although the protective role of dietary fiber on cancer risk has been reported in several epidemiological studies, the association of fiber intake on head and neck cancer (HNC) risk is still unclear. We investigated the association between fiber intake and the risk of HNC using data from the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial. Among 101,700 participants with complete dietary information, 186 participants developed HNC during follow-up (January 1998 to May 2011). Dietary data were collected using a self-administered food-frequency questionnaire (1998-2005). We estimated hazard ratios (HRs) and the corresponding 95% confidence intervals (CI), using the Cox proportional hazards model. Higher intake of total fiber, insoluble fiber and soluble fiber was associated with decreased HNC risks, with a significant trend. The HRs of highest vs. the lowest tertile of intake were 0.43 (95%CI: 0.25-0.76) for total fiber, 0.38 (95%CI: 0.22-0.65) for insoluble fiber, and 0.44 (95%CI: 0.25-0.79) for soluble fiber. These inverse association were consistent in oral cavity and pharyngeal cases, but the impact of fiber intake was weaker in laryngeal cases. We did not observe any significant interaction of potential confounders, including smoking and drinking, with total fiber intake on HNC risk. These findings support evidence of a protective role of dietary fiber on HNC risk.
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http://dx.doi.org/10.1002/ijc.32162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771385PMC
November 2019

Tobacco smoking, alcohol drinking, betel quid chewing, and the risk of head and neck cancer in an East Asian population.

Head Neck 2019 01 15;41(1):92-102. Epub 2018 Dec 15.

Division of Public Health, Department of Family and Preventive Medicine, and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah.

Background: The smoking prevalence among men in China is high, but the head and neck cancer incidence rates are low. This study's purpose was to investigate the impact of tobacco, betel quid, and alcohol on head and neck cancer risk in East Asia.

Methods: A multicenter case-control study (921 patients with head and neck cancer and 806 controls) in East Asia was conducted. The odds ratio (OR) and 95% confidence interval (CI) were estimated using logistic regression.

Results: Head and neck cancer risks were elevated for tobacco (OR = 1.58), betel quid (OR = 8.23), and alcohol (OR = 2.29). The total attributable risk of tobacco and/or alcohol was 47.2%. Tobacco/alcohol appeared to account for a small proportion of head and neck cancer among women (attributable risk of 2.2%). Betel quid chewing alone accounted for 28.7% of head and neck cancer.

Conclusions: Betel quid chewing is the strongest risk factor for oral cavity cancer in this Chinese population. Alcohol may play a larger role for head and neck cancer in this population than in European or U.S.

Populations:
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http://dx.doi.org/10.1002/hed.25383DOI Listing
January 2019

Alcohol consumption and lung cancer risk: A pooled analysis from the International Lung Cancer Consortium and the SYNERGY study.

Cancer Epidemiol 2019 02 13;58:25-32. Epub 2018 Nov 13.

University Institute of Oncology (IUOPA), University of Oviedo, and CIBERESP, Spain.

Background: There is inadequate evidence to determine whether there is an effect of alcohol consumption on lung cancer risk. We conducted a pooled analysis of data from the International Lung Cancer Consortium and the SYNERGY study to investigate this possible association by type of beverage with adjustment for other potential confounders.

Methods: Twenty one case-control studies and one cohort study with alcohol-intake data obtained from questionnaires were included in this pooled analysis (19,149 cases and 362,340 controls). Adjusted odds ratios (OR) or hazard ratios (HR) with corresponding 95% confidence intervals (CI) were estimated for each measure of alcohol consumption. Effect estimates were combined using random or fixed-effects models where appropriate. Associations were examined for overall lung cancer and by histological type.

Results: We observed an inverse association between overall risk of lung cancer and consumption of alcoholic beverages compared to non-drinkers, but the association was not monotonic. The lowest risk was observed for persons who consumed 10-19.9 g/day ethanol (OR vs. non-drinkers = 0.78; 95% CI: 0.67, 0.91), where 1 drink is approximately 12-15 g. This J-shaped association was most prominent for squamous cell carcinoma (SCC). The association with all lung cancer varied little by type of alcoholic beverage, but there were notable differences for SCC. We observed an association with beer intake (OR for ≥20 g/day vs nondrinker = 1.42; 95% CI: 1.06, 1.90).

Conclusions: Whether the non-monotonic associations we observed or the positive association between beer drinking and squamous cell carcinoma reflect real effects await future analyses and insights about possible biological mechanisms.
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http://dx.doi.org/10.1016/j.canep.2018.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662590PMC
February 2019

Non-mitotic effect of albendazole triggers apoptosis of human leukemia cells via SIRT3/ROS/p38 MAPK/TTP axis-mediated TNF-α upregulation.

Biochem Pharmacol 2019 04 7;162:154-168. Epub 2018 Nov 7.

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. Electronic address:

Albendazole (ABZ) is a microtubule-targeting anthelmintic that acts against a variety of human cancer cells, but the dependence of its cytotoxicity on non-mitotic effect remains elusive. Thus, we aimed to explore the mechanistic pathway underlying the cytotoxicity of ABZ in human leukemia U937 cells. ABZ-induced apoptosis of U937 cells was characterized by mitochondrial ROS generation, p38 MAPK activation, TNF-α upregulation and activation of the death receptor-mediated pathway. Meanwhile, ABZ induced tubulin depolymerization and G2/M cell cycle arrest. ABZ-induced SIRT3 degradation elicited ROS-mediated p38 MAPK activation, leading to pyruvate kinase M2-mediated tristetraprolin (TTP) degradation. Inhibition of TTP-mediated TNF-α mRNA decay elicited TNF-α upregulation in ABZ-treated cells. Either the overexpression of SIRT3 or abolishment of ROS/p38 MAPK activation suppressed TNF-α upregulation and rescued the viability of ABZ-treated cells. In contrast to the inhibition of ROS/p38 MAPK pathway, SIRT3 overexpression attenuated tubulin depolymerization and G2/M arrest in ABZ-treated cells. Treatment with a SIRT3 inhibitor induced TNF-α upregulation and cell death without the induction of G2/M arrest in U937 cells. Taken together, our data indicate that ABZ-induced SIRT3 downregulation promotes its microtubule-destabilizing effect, and that the non-mitotic effect of ABZ largely triggers apoptosis of U937 cells via SIRT3/ROS/p38 MAPK/TTP axis-mediated TNF-α upregulation. Notably, the same pathway is involved in the ABZ-induced death of HL-60 cells.
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http://dx.doi.org/10.1016/j.bcp.2018.11.003DOI Listing
April 2019

The suppressive effect of arsenic trioxide on TET2-FOXP3-Lyn-Akt axis-modulated MCL1 expression induces apoptosis in human leukemia cells.

Toxicol Appl Pharmacol 2018 11 10;358:43-55. Epub 2018 Sep 10.

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. Electronic address:

Arsenic trioxide (ATO) has been reported to inhibit the activity of Ten-eleven translocation methylcytosine dioxygenase (TET). TET modulates FOXP3 expression, while dysregulation of FOXP3 expression promotes the malignant progression of leukemia cells. We examined the role of TET-FOXP3 axis in the cytotoxic effects of ATO on the human acute myeloid leukemia cell line, U937. ATO-induced apoptosis in U937 cells was characterized by activation of caspase-3/-9, mitochondrial depolarization, and MCL1 downregulation. In addition, ATO-treated U937 cells showed ROS-mediated inhibition of TET2 transcription, leading to downregulation of FOXP3 expression and in turn, suppression of FOXP3-mediated activation of Lyn and Akt. Overexpression of FOXP3 or Lyn minimized the suppressive effect of ATO on Akt activation and MCL1 expression. Promoter luciferase activity and chromatin immunoprecipitation assays revealed the crucial role of Akt-mediated CREB phosphorylation in MCL1 transcription. Further, ATO-induced Akt inactivation promoted GSK3β-mediated degradation of MCL1. Transfection of constitutively active Akt expression abrogated ATO-induced MCL1 downregulation. MCL1 overexpression lessened the ATO-induced depolarization of mitochondrial membrane and increased the viability of ATO-treated cells. Thus, our data suggest that ATO induces mitochondria-mediated apoptosis in U937 cells through its suppressive effect on TET2-FOXP3-Lyn-Akt axis-modulated MCL1 transcription and protein stabilization. Our findings also indicate that the same pathway underlies ATO-induced death in human leukemia HL-60 cells.
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http://dx.doi.org/10.1016/j.taap.2018.09.008DOI Listing
November 2018

Shared and Study-specific Dietary Patterns and Head and Neck Cancer Risk in an International Consortium.

Epidemiology 2019 01;30(1):93-102

Branch of Medical Statistics, Biometry and Epidemiology "G. A. Maccacaro," Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy.

Background: A few papers have considered reproducibility of a posteriori dietary patterns across populations, as well as pattern associations with head and neck cancer risk when multiple populations are available.

Methods: We used individual-level pooled data from seven case-control studies (3844 cases; 6824 controls) participating in the International Head and Neck Cancer Epidemiology consortium. We simultaneously derived shared and study-specific a posteriori patterns with a novel approach called multi-study factor analysis applied to 23 nutrients. We derived odds ratios (ORs) and 95% confidence intervals (CIs) for cancers of the oral cavity and pharynx combined, and larynx, from logistic regression models.

Results: We identified three shared patterns that were reproducible across studies (75% variance explained): the Antioxidant vitamins and fiber (OR = 0.57, 95% CI = 0.41, 0.78, highest versus lowest score quintile) and the Fats (OR = 0.80, 95% CI = 0.67, 0.95) patterns were inversely associated with oral and pharyngeal cancer risk. The Animal products and cereals (OR = 1.5, 95% CI = 1.1, 2.1) and the Fats (OR = 1.8, 95% CI = 1.4, 2.3) patterns were positively associated with laryngeal cancer risk, whereas a linear inverse trend in laryngeal cancer risk was evident for the Antioxidant vitamins and fiber pattern. We also identified four additional study-specific patterns, one for each of the four US studies examined. We named them all as Dairy products and breakfast cereals, and two were associated with oral and pharyngeal cancer risk.

Conclusion: Multi-study factor analysis provides insight into pattern reproducibility and supports previous evidence on cross-country reproducibility of dietary patterns and on their association with head and neck cancer risk. See video abstract at, http://links.lww.com/EDE/B430.
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http://dx.doi.org/10.1097/EDE.0000000000000902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269206PMC
January 2019

ABT-263-induced MCL1 upregulation depends on autophagy-mediated 4EBP1 downregulation in human leukemia cells.

Cancer Lett 2018 09 15;432:191-204. Epub 2018 Jun 15.

Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, 807, Taiwan. Electronic address:

The present study aimed to investigate the pathway related to MCL1 expression in ABT-263-treated human leukemia U937 cells. ABT-263 upregulated MCL1 protein expression but did not affect its mRNA level and protein stability. Notably, ABT-263 increased 4EBP1 mRNA decay and thus reduced 4EBP1 expression. Overexpression of 4EBP1 abrogated ABT-263-induced MCL1 upregulation. ABT-263-induced activation of IKKα/β-NFκB axis elicited autophagy of U937 cells, leading to reduced mRNA stability of 4EBP1. Inhibition of the IKKα/β-NFκB axis or autophagy mitigated the effect of ABT-263 on 4EBP1 and MCL1 expression. Amsacrine enhanced the cytotoxicity of ABT-263 in human leukemia U937, HL-60, and Jurkat cells because of its inhibitory effect on the IKKα/β-NFκB-mediated pathway. Our data indicate that ABT-263 alleviates the inhibitory effect of 4EBP1 on MCL1 protein synthesis through IKKα/β-NFκB-mediated induction of autophagy, and suggest a promising strategy to improve anti-leukemia therapy with ABT-263.
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http://dx.doi.org/10.1016/j.canlet.2018.06.019DOI Listing
September 2018

Tumour stage and gender predict recurrence and second primary malignancies in head and neck cancer: a multicentre study within the INHANCE consortium.

Eur J Epidemiol 2018 Dec 19;33(12):1205-1218. Epub 2018 May 19.

Section of Hygiene, Institute of Public Health, Università Cattolica del Sacro Cuore, Fondazione Policlinico "Agostino Gemelli" IRCCS, Largo F. Vito, 1, 00168, Rome, Italy.

Recurrence and second primary cancer (SPC) continue to represent major obstacles to long-term survival in head and neck cancer (HNC). Our aim was to evaluate whether established demographics, lifestyle-related risk factors for HNC and clinical data are associated with recurrence and SPC in HNC. We conducted a multicentre study by using data from five studies members of the International Head and Neck Cancer Epidemiology consortium-Milan, Rome, Western Europe, Sao Paulo, and Japan, totalling 4005 HNC cases with a median age of 59 (interquartile range 52-67). Multivariate hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for recurrence and SPC. During follow-up, 1161 (29%) patients had recurrence and 343 (8.6%) developed SPC. Advanced tumour stage was associated with increased risk of recurrence in HNC overall (HR = 1.76, 95% CI 1.41-2.19). Women with laryngeal cancer had a reduced risk of recurrence compared to men (HR = 0.39, 95% CI: 0.24-0.74). Concerning predictors of SPC, advanced age (HR = 1.02; 95% CI: 1.00-1.04) and alcohol consumption (> 1 drink per day, HR = 2.11; 95% CI: 1.13-3.94) increased the risk of SPC among patients with laryngeal cancer. Additionally, women were at higher risk of SPC, in HNC overall group (HR = 1.68; 95% CI: 1.13-2.51) and oropharyngeal cancer group (HR = 1.74; 95% CI: 1.02-2.98). Tumour stage and male gender (larynx only) were positive predictors of cancer recurrence in HNC patients. Predictors of SPC were advanced age and alcohol use among laryngeal cancer cases, and female gender for oropharyngeal and HNC overall.
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http://dx.doi.org/10.1007/s10654-018-0409-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6290648PMC
December 2018