Publications by authors named "Ji-Hoon Jung"

117 Publications

Inhibition of CNOT2 Induces Apoptosis via MID1IP1 in Colorectal Cancer Cells by Activating p53.

Biomolecules 2021 Oct 10;11(10). Epub 2021 Oct 10.

College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea.

CCR4-NOT transcription complex subunit 2 (CNOT2), a subunit of the CCR4-NOT complex, has been described in cancer progression. The CNOT complex plays an important role in multiple cellular functions. Recent studies in our laboratory showed that CNOT2 promotes breast cancer cell proliferation and angiogenesis. In addition, CNOT2 signals are critically related to apoptosis induced by atorvastatin in lung cancer cells. Furthermore, depletion of CNOT2 was shown to enhance the antitumor effect of midline 1 interacting protein 1 (MID1IP1) depletion, thus inhibiting c-Myc expression in liver cancer cells. However, the molecular mechanisms related to its oncogenic role remain unclear. Herein, for the first time, we report that CNOT2 inhibition can induce apoptosis in colorectal cancer cells by activating p53. Inhibition of CNOT2 markedly induced apoptosis in various cancer cells like that of the wild-type p53. Furthermore, inhibition of CNOT2 elongated p53 s half-life. Previously, our laboratory demonstrated that MID1IP1 promoted colocalization with c-Myc mediated by CNOT2. Interestingly, inhibition of CNOT2 cannot induce p53 expression without MID1IP1 or apoptosis in cancer cells. In conclusion, our results demonstrate that CNOT2 inhibition induces apoptosis through MID1IP1 by activating p53.
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http://dx.doi.org/10.3390/biom11101492DOI Listing
October 2021

Multivessel versus IRA-only PCI in patients with NSTEMI and severe left ventricular systolic dysfunction.

PLoS One 2021 13;16(10):e0258525. Epub 2021 Oct 13.

Korea Institute of Toxicology, Daejeon, Republic of Korea.

Background: A substantial number of patients presenting with non-ST-elevation myocardial infarction (NSTEMI) and multivessel disease (MVD) have severe left ventricular systolic dysfunction (LVSD) (left ventricular ejection fraction (LVEF) less than 35%). But data are lacking regarding optimal percutaneous coronary intervention (PCI) strategy for these patients. The aim of this study was to compare the long-term outcomes of IRA (infarct-related artery)-only and multivessel PCI in patients with NSTEMI and MVD complicated by severe LVSD.

Methods: Among 13,104 patients enrolled in the PCI registry from November 2011 to December 2015, patients with NSTEMI and MVD with severe LVSD who underwent successful PCI were screened. The primary outcome was 3-year major adverse cardiovascular events (MACEs), defined as all-cause death, any myocardial infarction, stroke, and any revascularization.

Results: Overall, 228 patients were treated with IRA-only PCI (n = 104) or MV-PCI (n = 124). The MACE risk was significantly lower in the MV-PCI group than in the IRA-only PCI group (35.5% vs. 54.8%; hazard ratio [HR] 0.561; 95% confidence interval [CI] 0.378-0.832; p = 0.04). This result was mainly driven by a significantly lower risk of all-cause death (23.4% vs. 41.4%; hazard ratio [HR] 0.503; 95% confidence interval [CI] 0.314-0.806; p = 0.004). The results were consistent after multivariate regression, propensity-score matching, and inverse probability weighting to adjust for baseline differences.

Conclusions: Among patients with NSTEMI and MVD complicated with severe LVSD, multivessel PCI was associated with a significantly lower MACE risk. The findings may provide valuable information to physicians who are involved in decision-making for these patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0258525PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8513855PMC
October 2021

Anti-Obesity Effect of Polygalin C Isolated from Houtt. via Suppression of the Adipogenic and Lipogenic Factors in 3T3-L1 Adipocytes.

Int J Mol Sci 2021 Sep 27;22(19). Epub 2021 Sep 27.

College of Korean Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea.

Obesity is a risk factor for metabolic diseases including type 2 diabetes, nonalcoholic steatohepatitis (NASH), heart diseases, and cancer. This study aimed to investigate the anti-obesity effect of Polygalin C (PC) isolated from Houtt. in 3T3-L1 adipocytes. Based on Oil Red O assay results, PC significantly decreased lipid accumulation compared to the control. We found that PC suppressed adipogenesis transcription factors including peroxisome proliferator-activated receptor γ (PPAR γ) and CCAAT/enhancer-binding protein (C/EBP) α, and lipogenic factors such as sterol regulatory element-binding protein 1c (SREBP 1c) and fatty acid synthase (FAS), in 3T3-L1 adipocytes using Western blotting and real-time polymerase chain reaction (PCR). Moreover, PC inhibited the differentiation of 3T3-L1 cells by regulating the AMP-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) and mitogen-activated protein kinase/protein kinase B (MAPK/Akt) signaling pathways. Additionally, we confirmed that PC inhibited early adipogenesis factors C/EBP β and C/EBP δ. Therefore, PC inhibited adipogenesis and lipogenesis in vitro. Thus, PC appears to exert potential therapeutic effects on obesity by suppressing lipid metabolism.
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http://dx.doi.org/10.3390/ijms221910405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508696PMC
September 2021

UBE2M Drives Hepatocellular Cancer Progression as a p53 Negative Regulator by Binding to MDM2 and Ribosomal Protein L11.

Cancers (Basel) 2021 Sep 29;13(19). Epub 2021 Sep 29.

Molecular Cancer Target Herbal Research Laboratory, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea.

Though UBE2M, an E2 NEDD8-conjugating enzyme, is overexpressed in HepG2, Hep3B, Huh7 and PLC/PRF5 HCCs with poor prognosis by human tissue array and TCGA analysis, its underlying oncogenic mechanism remains unclear. Herein, UBE2M depletion suppressed viability and proliferation and induced cell cycle arrest and apoptosis via cleavages of PARP and caspase 3 and upregulation of p53, Bax and PUMA in HepG2, Huh7 and Hep3B cells. Furthermore, UBE2M depletion activated p53 expression and stability, while the ectopic expression of UBE2M disturbed p53 activation and enhanced degradation of exogenous p53 mediated by MDM2 in HepG2 cells. Interestingly, UBE2M binds to MDM2 or ribosomal protein L11, but not p53 in HepG2 cells, despite crosstalk between p53 and UBE2M. Consistently, the colocalization between UBE2M and MDM2 was observed by immunofluorescence. Notably, L11 was required in p53 activation by UBE2M depletion. Furthermore, UBE2M depletion retarded the growth of HepG2 cells in athymic nude mice along with elevated p53. Overall, these findings suggest that UBE2M promotes cancer progression as a p53 negative regulator by binding to MDM2 and ribosomal protein L11 in HCCs.
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http://dx.doi.org/10.3390/cancers13194901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8507934PMC
September 2021

Gancaonin N from Attenuates the Inflammatory Response by Downregulating the NF-κB/MAPK Pathway on an Acute Pneumonia In Vitro Model.

Pharmaceutics 2021 Jul 6;13(7). Epub 2021 Jul 6.

College of Korean Medicine, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea.

Acute pneumonia is an inflammatory disease caused by several pathogens, with symptoms such as fever and chest pain, to which children are particularly vulnerable. Gancaonin N is a prenylated isoflavone of that has been used in the treatment of various diseases in oriental medicine. There are little data on the anti-inflammatory efficacy of Gancaonin N, and its effects and mechanisms on acute pneumonia are unknown. Therefore, this study was conducted as a preliminary analysis of the anti-inflammatory effect of Gancaonin N in lipopolysaccharide (LPS)-induced RAW264.7 cells, and to identify its preventive effect on the lung inflammatory response and the molecular mechanisms underlying it. In this study, Gancaonin N inhibited the production of NO and PGE2 in LPS-induced RAW264.7 cells and significantly reduced the expression of iNOS and COX-2 proteins at non-cytotoxic concentrations. In addition, in LPS-induced A549 cells, Gancaonin N significantly reduced the expression of COX-2 and pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6. Moreover, Gancaonin N reduced MAPK signaling pathway phosphorylation and NF-κB nuclear translocation. Therefore, Gancaonin N relieved the inflammatory response by inactivating the MAPK and NF-κB signaling pathways; thus, it is a potential natural anti-inflammatory agent that can be used in the treatment of acute pneumonia.
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http://dx.doi.org/10.3390/pharmaceutics13071028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8309055PMC
July 2021

Clinical Outcome of Rotational Atherectomy in Calcified Lesions in Korea-ROCK Registry.

Medicina (Kaunas) 2021 Jul 7;57(7). Epub 2021 Jul 7.

Department of Cardiology, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.

: Data is still limited regarding clinical outcomes of rotational atherectomy (RA) after percutaneous coronary intervention. We sought to evaluate clinical outcomes of RA. This multi-center registry enrolled patients who underwent RA during PCI from nine tertiary centers in Korea between January 2010 and October 2019. The primary endpoint was target-vessel failure (TVF; the composite outcome of cardiac death, target-vessel spontaneous myocardial infarction, or target-vessel revascularization). : Of 540 patients (583 lesions), the mean patient age was 71.4 ± 0.4 years, 323 patients (59.8%) were men, and 305 patients (56.5%) had diabetes mellitus. Technical success rate was 96.4%. In-hospital major adverse cerebral and cardiac events occurred in 63 cases (10.8%). At 1.5 years, 72 (16.0%) of TVFs were occurred. We evaluated independent predictors of TVF, which included current smoker (hazard ratio (HR), 1.92; 95% confidence interval (CI), 1.17-3.16; = 0.01), chronic renal disease (HR, 1.87; 95% CI, 1.14-3.08; = 0.013), history of cerebrovascular attack (HR, 2.14; 95% CI, 1.24-3.68; = 0.006), left ventricle ejection fraction (HR, 0.98; 95% CI, 0.97-0.999; = 0.037), and left main disease (HR, 1.94; 95% CI, 1.11-3.37; = 0.019). From this registry, we demonstrated acceptable success rates, in-hospital and mid-term clinical outcomes of RA in the DES era.
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http://dx.doi.org/10.3390/medicina57070694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303478PMC
July 2021

Ferulic Acid Induces Keratin 6α via Inhibition of Nuclear β-Catenin Accumulation and Activation of Nrf2 in Wound-Induced Inflammation.

Biomedicines 2021 Apr 22;9(5). Epub 2021 Apr 22.

Department of Science in Korean Medicine, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea.

Injured tissue triggers complex interactions through biological process associated with keratins. Rapid recovery is most important for protection against secondary infection and inflammatory pain. For rapid wound healing with minimal pain and side effects, shilajit has been used as an ayurvedic medicine. However, the mechanisms of rapid wound closure are unknown. Here, we found that shilajit induced wound closure in an acute wound model and induced migration in skin explant cultures through evaluation of transcriptomics via microarray testing. In addition, ferulic acid (FA), as a bioactive compound, induced migration via modulation of keratin 6α (K6α) and inhibition of β-catenin in primary keratinocytes of skin explant culture and injured full-thickness skin, because accumulation of β-catenin into the nucleus acts as a negative regulator and disturbs migration in human epidermal keratinocytes. Furthermore, FA alleviated wound-induced inflammation via activation of nuclear factor erythroid-2-related factor 2 (Nrf2) at the wound edge. These findings show that FA is a novel therapeutic agent for wound healing that acts via inhibition of β-catenin in keratinocytes and by activation of Nrf2 in wound-induced inflammation.
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http://dx.doi.org/10.3390/biomedicines9050459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146113PMC
April 2021

Gender differences in clinical outcomes of acute myocardial infarction undergoing percutaneous coronary intervention: insights from the KAMIR-NIH Registry.

J Geriatr Cardiol 2020 Nov;17(11):680-693

Division of Cardiology, Daejeon St. Mary's hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea.

Background: There are numerous but conflicting data regarding gender differences in outcomes following percutaneous coronary intervention (PCI). Furthermore, gender differences in clinical outcomes with acute myocardial infarction (AMI) following PCI in Asian population remain uncertain because of the under-representation of Asian in previous trials.

Methods: A total of 13, 104 AMI patients from Korea Acute Myocardial Infarction Registry-National Institute of Health (KAMIR-NIH) between November 2011 and December 2015 were classified into male ( = 8021, 75.9%) and female ( = 2547, 24.1%). We compared the demographic, clinical and angiographic characteristics, 30-days and 1-year major adverse cardiac and cerebrovascular events (MACCE) in women with those in men after AMI by using propensity score (PS) matching.

Results: Compared with men, women were older, had more comorbidities and more often presented with non-ST segment elevation myocardial infarction (NSTEMI) and reduced left ventricular systolic function. Over the median follow-up of 363 days, gender differences in both 30-days and 1-year MACCE as well as thrombolysis in myocardial infarction minor bleeding risk were not observed in the PS matched population (30-days MACCE: 5.3% . 4.7%, log-rank = 0.494, HR = 1.126, 95% CI: 0.800-1.585; 1-year MACCE: 9.3% . 9.0%, log-rank = 0.803, HR = 1.032, 95% CI: 0.802-1.328; TIMI minor bleeding: 4.9% . 3.9%, log-rank = 0.215, HR = 1.255, 95% CI: 0.869-1.814).

Conclusions: Among Korean AMI population undergoing contemporary PCI, women, as compared with men, had different clinical and angiographic characteristics but showed similar 30-days and 1-year clinical outcomes. The risk of bleeding after PCI was comparable between men and women during one-year follow up.
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http://dx.doi.org/10.11909/j.issn.1671-5411.2020.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729180PMC
November 2020

RBM10, a New Regulator of p53.

Cells 2020 09 16;9(9). Epub 2020 Sep 16.

Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA.

The tumor suppressor p53 acts as a transcription factor that regulates the expression of a number of genes responsible for DNA repair, cell cycle arrest, metabolism, cell migration, angiogenesis, ferroptosis, senescence, and apoptosis. It is the most commonly silenced or mutated gene in cancer, as approximately 50% of all types of human cancers harbor TP53 mutations. Activation of p53 is detrimental to normal cells, thus it is tightly regulated via multiple mechanisms. One of the recently identified regulators of p53 is RNA-binding motif protein 10 (RBM10). RBM10 is an RNA-binding protein frequently deleted or mutated in cancer cells. Its loss of function results in various deformities, such as cleft palate and malformation of the heart, and diseases such as lung adenocarcinoma. In addition, RBM10 mutations are frequently observed in lung adenocarcinomas, colorectal carcinomas, and pancreatic ductal adenocarcinomas. RBM10 plays a regulatory role in alternative splicing. Several recent studies not only linked this splicing regulation of RBM10 to cancer development, but also bridged RBM10's anticancer function to the p53 pathway. This review will focus on the current progress in our understanding of RBM10 regulation of p53, and its role in p53-dependent cancer prevention.
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http://dx.doi.org/10.3390/cells9092107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563659PMC
September 2020

Ribosomal protein L5 mediated inhibition of c-Myc is critically involved in sanggenon G induced apoptosis in non-small lung cancer cells.

Phytother Res 2021 Feb 16;35(2):1080-1088. Epub 2020 Sep 16.

College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.

Though Sanggenon G (SanG) from root bark of Morus alba was known to exhibit anti-oxidant and anti-depressant effects, its underlying mechanisms still remain unclear. Herein SanG reduced the viability of A549 and H1299 non-small lung cancer cells (NSCLCs). Also, SanG increased sub-G1 population via inhibition of cyclin D1, cyclin E, CDK2, CDK4 and Bcl-2, cleavages of poly (ADP-ribose) polymerase (PARP) and caspase-3 in A549 and H1299 cells. Of note, SanG effectively inhibited c-Myc expression by activating ribosomal protein L5 (RPL5) and reducing c-Myc stability even in the presence of cycloheximide and 20% serum in A549 cells. Furthermore, SanG enhanced the apoptotic effect with doxorubicin in A549 cells. Taken together, our results for the first time provide novel evidence that SanG suppresses proliferation and induces apoptosis via caspase-3 activation and RPL5 mediated inhibition of c-Myc with combinational potential with doxorubicin.
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http://dx.doi.org/10.1002/ptr.6878DOI Listing
February 2021

MicroRNA216b mediated downregulation of HSP27/STAT3/AKT signaling is critically involved in lambertianic acid induced apoptosis in human cervical cancers.

Phytother Res 2021 Feb 21;35(2):898-907. Epub 2020 Aug 21.

College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.

Since heat shock protein (HSP27) is a prognostic marker in cervical cancer, in the present study, the apoptotic mechanism of lambertianic acid (LA) was investigated in human cervical cancers in association with HSP27/STAT3/AKT signaling axis. LA exerted significant cytotoxicity, induced sub-G1 population, and increased the cleavage of Poly (ADP-ribose) polymerase (PARP) and cysteine aspartyl-specific protease 3 (caspase3) in HeLa and Caski cancer cells. Consistently, LA downregulated anti-apopotic genes such as B-cell lymphoma 2 (Bcl-2) and inhibitors of apoptosis proteins (c-IAP) in HeLa and Caski cells. Furthermore, LA-inhibited phosphorylation of HSP27, signal transducer, and activator of transcription 3 (STAT3) and Protein kinase B (AKT) through disturbing the binding of HSP27 with STAT3 or AKT in HeLa cells. Notably, LA upregulated the level of miR216b in HeLa and Caski cells. Consistently, miR216b mimic suppressed phosphorylation of HSP27 and reduced the expression of pro-PARP, while miR216b inhibitor reversed the ability of LA to attenuate phosphorylation of AKT, HSP27, and STAT3 and to reduce the expression of pro-PARP in HeLa cells. Overall, our findings suggest that miRNA216b mediated inhibition of HSP27/STAT3/ AKT signaling axis is critically involved in LA-induced apoptosis in cervical cancers.
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http://dx.doi.org/10.1002/ptr.6842DOI Listing
February 2021

Apoptotic and antihepatofibrotic effect of honokiol via activation of GSK3β and suppression of Wnt/β-catenin pathway in hepatic stellate cells.

Phytother Res 2021 Jan 10;35(1):452-462. Epub 2020 Aug 10.

College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.

Though honokiol, derived from the Magnolia tree, was known to suppress renal fibrosis, pulmonary fibrosis, non-alcoholic steatoheptitis, inflammation and cancers, the underlying antifibrotic mechanisms of honokiol are not fully understood in hepatic stellate cells until now. Thus, in the present study, inhibitory mechanism of honokiol on liver fibrosis was elucidated mainly in hepatic stellate cells (HSCs) by 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, cell cycle analysis and western-blotting. Honokiol exerted cytotoxicity in LX-2, HSC-T6 and Hep-G2 cells. Honokiol increased sub G1 population and activated caspase 3 and cleaved poly (ADP-ribose) polymerase (PARP) in HSCs. Moreover, honokiol attenuated the expression of alpha smooth muscle actin (α-SMA), transforming growth factor beta 1 (TGF-β1), phospho-Smad3, phospho-AKT, cyclin D1, c-Myc, Wnt3a, β-catenin, and activated phosphorylation of glycogen synthase kinase 3 beta (GSK3β) in HSCs. Conversely, GSK3β inhibitor SB216763 reversed the effect of honokiol on PARP, α-SMA, phospho-GSK3β, β-catenin and sub G1 population in LX-2 cells. Overall, honokiol exerts apoptotic and antifibrotic effects via activation of GSK3β and inhibition of Wnt3a/β-catenin signalling pathway.
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http://dx.doi.org/10.1002/ptr.6824DOI Listing
January 2021

Corrigendum to "Activation of AMP-Activated Protein Kinase and Extracelluar Signal-Regulated Kinase Mediates CB-PIC-Induced Apoptosis in Hypoxic SW620 Colorectal Cancer Cells".

Evid Based Complement Alternat Med 2020 11;2020:6289392. Epub 2020 Jul 11.

College of Oriental Medicine, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Republic of Korea.

[This corrects the article DOI: 10.1155/2013/974313.].
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http://dx.doi.org/10.1155/2020/6289392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400768PMC
July 2020

p53 dependent LGR5 inhibition and caspase 3 activation are critically involved in apoptotic effect of compound K and its combination therapy potential in HCT116 cells.

Phytother Res 2020 Oct 13;34(10):2745-2755. Epub 2020 May 13.

College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.

Though ginsenoside metabolite compound K was known to have antitumor effect in several cancers, its underlying apoptotic mechanism still remains unclear so far. Thus, in the present study, the apoptotic mechanism of compound K was explored in colorectal cancer cells (CRCs) in association with leucine rich repeat containing G protein-coupled receptor 5 (LGR5) that was overexpressed in colorectal cancers with poor survival rate. Here compound K significantly reduced viability of HCT116 cells better than that of HCT116 cells. Consistently, compound K increased sub G1 population and attenuated the expression of LGR5, c-Myc, procaspase3, Pin1 in HCT116 cells more than in HCT116 cells. Conversely, caspase 3 inhibitor Z-DEVD-FMK reversed inhibitory effect of compound K on LGR5, c-Myc and procaspase3 in HCT116 cells. Consistently, inhibition of LGR5 using transfection method enhanced suppression of pro-PARP, Bcl-x c-Myc, Snail and Pin1 in compound K treated HCT116 cells. Furthermore, compound K synergistically potentiated antitumor effect of 5-fluorouracil (5-FU) or Doxorubicin to reduce the survival genes and cytotoxicity in HCT116 cells. Overall, our findings provide scientific insight that compound K induces apoptosis in colon cancer cells via caspase and p53 dependent LGR5 inhibition with combination therapy potential with 5-FU or doxorubicin.
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http://dx.doi.org/10.1002/ptr.6717DOI Listing
October 2020

Colocalization of MID1IP1 and c-Myc is Critically Involved in Liver Cancer Growth via Regulation of Ribosomal Protein L5 and L11 and CNOT2.

Cells 2020 04 16;9(4). Epub 2020 Apr 16.

Cancer Molecular Targeted Herbal Research Laboratory, College of Korean Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea.

Though midline1 interacting protein 1 (MID1IP1) was known as one of the glucose-responsive genes regulated by carbohydrate response element binding protein (ChREBP), the underlying mechanisms for its oncogenic role were never explored. Thus, in the present study, the underlying molecular mechanism of MID1P1 was elucidated mainly in HepG2 and Huh7 hepatocellular carcinoma cells (HCCs). MID1IP1 was highly expressed in HepG2, Huh7, SK-Hep1, PLC/PRF5, and immortalized hepatocyte LX-2 cells more than in normal hepatocyte AML-12 cells. MID1IP1 depletion reduced the viability and the number of colonies and also increased sub G1 population and the number of TUNEL-positive cells in HepG2 and Huh7 cells. Consistently, MID1IP1 depletion attenuated pro-poly (ADP-ribose) polymerase (pro-PARP), c-Myc and activated p21, while MID1IP1 overexpression activated c-Myc and reduced p21. Furthermore, MID1IP1 depletion synergistically attenuated c-Myc stability in HepG2 and Huh7 cells. Of note, MID1IP1 depletion upregulated the expression of ribosomal protein L5 or L11, while loss of L5 or L11 rescued c-Myc in MID1IP1 depleted HepG2 and Huh7 cells. Interestingly, tissue array showed that the overexpression of MID1IP1 was colocalized with c-Myc in human HCC tissues, which was verified in HepG2 and Huh7 cells by Immunofluorescence. Notably, depletion of CCR4-NOT2 (CNOT2) with adipogenic activity enhanced the antitumor effect of MID1IP1 depletion to reduce c-Myc, procaspase 3 and pro-PARP in HepG2, Huh7 and HCT116 cells. Overall, these findings provide novel insight that MID1IP1 promotes the growth of liver cancer via colocalization with c-Myc mediated by ribosomal proteins L5 and L11 and CNOT2 as a potent oncogenic molecule.
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http://dx.doi.org/10.3390/cells9040985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227012PMC
April 2020

Epigallocatechin-3-Gallate Induces Apoptosis as a TRAIL Sensitizer via Activation of Caspase 8 and Death Receptor 5 in Human Colon Cancer Cells.

Biomedicines 2020 Apr 9;8(4). Epub 2020 Apr 9.

College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea.

Though epigallocatechin-3-gallate (EGCG), a major compound of green tea, has anti-diabetes, anti-obesity, anti-inflammatory, and antitumor effects, the underlying antitumor molecular mechanism of EGCG was not fully understood so far. Here the sensitizing effect of EGCG to tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) was examined in colorectal cancers. Cotreatment of EGCG and TRAIL synergistically enhanced cytotoxicity and sub G1 accumulation, increased the number of terminal deoxynucleotidyl transferase-dT-mediated dUTP nick end labelling (TUNEL)-positive cells in SW480 and HCT116 cells. Furthermore, this cotreatment promoted the cleavages of poly (adenosine diphosphate-ribose) polymerase (PARP) and induced caspase 8 activation compared to TRAIL or EGCG alone in SW480 and HCT116 cells. Of note, cotreatment of EGCG and TRAIL increased the expression of death receptor 5 (DR5) at protein and mRNA levels and also DR5 cell surface level in colon cancer cells. Conversely, depletion of DR5 reduced the apoptotic activity of cotreatment of EGCG and TRAIL to increase cytotoxicity, sub-G1 population and PARP cleavages in colon cancer cells. Overall, our findings provide evidence that EGCG can be a sensitizer of TRAIL via DR5 and caspase 8 mediated apoptosis in colorectal cancer cells.
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http://dx.doi.org/10.3390/biomedicines8040084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235876PMC
April 2020

Misaponin B Induces G2/M Arrest, Cytokinesis Failure and Impairs Autophagy.

Biomed Res Int 2020 7;2020:5925094. Epub 2020 Feb 7.

College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea.

Saponins are a group of naturally occurring plant glycosides with the features of their strong foam-forming properties and multibiological effects such as antitumor activity. Though Misaponin B, one of the triterpenoid saponins from , is known to have spermicidal and antioxidant activity, the other biological activities have been never reported so far. Thus, in the present study, the antitumor mechanism of Misaponin B was investigated in A549 and AsPC-1 cancer cells. Misaponin B exerted significant cytotoxicity in A549, H460, SKOV3, and AsPC-1 cancer cells. Among them, A549 and AsPC-1 cells were more susceptible to Misaponin B. Misaponin B induced G2/M arrest and cytokinesis failure and increased the expression of LC3B and p62 with autophagic vacuoles and GFP-LC3 punctae in A549 and AsPC-1 cells. Furthermore, Misaponin B suppressed autophagy flux in A549 cells transfected by GFP-mRFP-LC3 constructs by showing merged yellow color by autophagy flux assay. Overall, our findings provide evidences that Misaponin B induces G2M arrest and impairs autophagy in A549 and AsPC-1 cells.
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http://dx.doi.org/10.1155/2020/5925094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029305PMC
November 2020

Crotonylation at serine 46 impairs p53 activity.

Biochem Biophys Res Commun 2020 04 5;524(3):730-735. Epub 2020 Feb 5.

Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA, 70112, USA; Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, 70112, USA. Electronic address:

Post-translational modifications (PTMs) play pivotal roles in controlling the stability and activity of the tumor suppressor p53 in response to distinct stressors. Here we report an unexpected finding of a short chain fatty acid modification of p53 in human cells. Crotonic acid (CA) treatment induces p53 crotonylation, but surprisingly reduces its protein, but not mRNA level, leading to inhibition of p53 activity in a dose dependent fashion. Surprisingly this crotonylation targets serine 46, instead of any predicted lysine residues, of p53, as detected in TCEP-probe labeled crotonylation and anti-crotonylated peptide antibody reaction assays. This is further confirmed by substitution of serine 46 with alanine, which abolishes p53 crotonylation in vitro and in cells. CA increases p53-dependent glycolytic activity, and augments cancer cell proliferation in response to metabolic or DNA damage stress. Since serine 46 is only found in human p53, our studies unveil an unconventional PTM unique for human p53, impairing its activity in response to CA. Because CA is likely produced by the gut microbiome, our results also predict that this type of PTM might play a role in early human colorectal neoplasia development by negating p53 activity without mutation of this tumor suppressor gene.
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http://dx.doi.org/10.1016/j.bbrc.2020.01.152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703795PMC
April 2020

Phyotochemical candidates repurposing for cancer therapy and their molecular mechanisms.

Semin Cancer Biol 2021 Jan 26;68:164-174. Epub 2019 Dec 26.

Cancer Molecular Target Herbal Research Laboratory, College of Korean Medicine, Seoul 02447, Republic of Korea. Electronic address:

Though limited success through chemotherapy, radiotherapy and surgery has been obtained for efficient cancer therapy for modern decades, cancers are still considered high burden to human health worldwide to date. Recently repurposing drugs are attractive with lower cost and shorter time compared to classical drug discovery, just as Metformin from Galega officinalis, originally approved for treating Type 2 diabetes by FDA, is globally valued at millions of US dollars for cancer therapy. As most previous reviews focused on FDA approved drugs and synthetic agents, current review discussed the anticancer potential of phytochemicals originally approved for treatment of cardiovascular diseases, diabetes, infectious diarrhea, depression and malaria with their molecular mechanisms and efficacies and suggested future research perspectives.
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http://dx.doi.org/10.1016/j.semcancer.2019.12.009DOI Listing
January 2021

Molecular networks of FOXP family: dual biologic functions, interplay with other molecules and clinical implications in cancer progression.

Mol Cancer 2019 12 9;18(1):180. Epub 2019 Dec 9.

Cancer Molecular Target Herbal Research Lab, College of Korean Medicine, Kyung Hee university, 1 Hoegi-dong, Dongdaemun-gu, Seoul, 02447, Republic of Korea.

Though Forkhead box P (FOXP) transcription factors comprising of FOXP1, FOXP2, FOXP3 and FOXP4 are involved in the embryonic development, immune disorders and cancer progression, the underlying function of FOXP3 targeting CD4 + CD25+ regulatory T (Treg) cells and the dual roles of FOXP proteins as an oncogene or a tumor suppressor are unclear and controversial in cancers to date. Thus, the present review highlighted research history, dual roles of FOXP proteins as a tumor suppressor or an oncogene, their molecular networks with other proteins and noncoding RNAs, cellular immunotherapy targeting FOXP3, and clinical implications in cancer progression.
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http://dx.doi.org/10.1186/s12943-019-1110-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900861PMC
December 2019

The Pivotal Role of Long Noncoding RNA RAB5IF in the Proliferation of Hepatocellular Carcinoma Via LGR5 Mediated β-Catenin and c-Myc Signaling.

Biomolecules 2019 11 8;9(11). Epub 2019 Nov 8.

College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea.

In the current study, the function of long noncoding RNA (LncRNA) RAB5IF was elucidated in hepatocellular carcinoma (HCCs) in association with LGR5 related signaling. Here TCGA analysis revealed that LncRNA RAB5IF was overexpressed in HCC, and its overexpression level was significantly ( < 0.05) correlated with poor prognosis in patients with HCC. Furthermore, LncRNA RAB5IF depletion suppressed cell proliferation and colony formation, increased sub G1 population, cleavage of poly ADP-ribose polymerase (PARP) and cysteine aspartyl-specific protease (caspase 3) and attenuated the expression of procaspase 3, pro-PARP and B-cell lymphoma 2 (Bcl-2) in HepG2 and Hep3B cells. Furthermore, LncRNA RAB5IF depletion reduced the expression of LGR5 and its downstreams such as β-catenin and c-Myc in HepG2 and Hep3B cells. Notably, LGR5 depletion also attenuated the expression of pro-PARP, pro-caspase3, β-catenin and c-Myc in HepG2 and Hep3B cells. Conversely, LGR5 overexpression upregulated β-catenin and c-Myc in Alpha Mouse Liver 12 (AML-12) normal hepatocytes. Overall, these findings provide novel evidence that LncRNA RAB5IF promotes the growth of hepatocellular carcinoma cells via LGR5 mediated β-catenin and c-Myc signaling as a potent oncogenic target.
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http://dx.doi.org/10.3390/biom9110718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920882PMC
November 2019

Farnesiferol C Induces Apoptosis in Chronic Myelogenous Leukemia Cells as an Imatinib Sensitizer via Caspase Activation and HDAC (Histone Deacetylase) Inactivation.

Int J Mol Sci 2019 Nov 6;20(22). Epub 2019 Nov 6.

College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea.

Herein the underlying apoptotic mechanism of Farnesiferol C (FC) derived from was elucidated in chronic myelogenous leukemia (CML) K562 and KBM5 cells. FC showed significant cytotoxicity in K562 and KBM5 cells, more so than in U937 and UL-60 acute myeloid leukemia (AML) cells. Cleaved PARP and caspase 9/3 attenuated the expression of Bcl2 and induced G1 arrest in K562 and KBM5 cells. Also, FC effectively abrogated the expression of cell cycle related proteins, such as: Cyclin D1, Cyclin E, Cyclin B1 in K562, and KBM5 cells, but caspase 3 inhibitor Z-DEVD-FMK rescued the cleavages of caspase 3 and PARP induced by FC in K562 cells. Of note, FC decreased histone deacetylase 1 (HDAC1) and HDAC2, and enhanced histone H3 acetylation K18 (Ac-H3K18) in K562 and KBM5 cells. Furthermore, combination of FC and Imatinib enhanced the apoptotic effect of Imatinib as a potent Imatinib sensitizer in K562 cells. Overall, our findings provide scientific evidence that inactivation of HDAC and caspase activation mediate FC induced apoptosis in CML cells.
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http://dx.doi.org/10.3390/ijms20225535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888363PMC
November 2019

Methyloleanolate Induces Apoptotic And Autophagic Cell Death Via Reactive Oxygen Species Generation And c-Jun N-terminal Kinase Phosphorylation.

Onco Targets Ther 2019 23;12:8621-8635. Epub 2019 Oct 23.

College of Korean Medicine, Kyung Hee University, Dongdaemun-Gu, Seoul 02447, Republic of Korea.

Background: To develop a potent anticancer agent similar to oleanolate, the underlying mechanisms of its derivative, methyloleanolate, in the apoptosis and autophagy of A549 and H1299 cells were elucidated.

Purpose: The aim of the present study was to investigate the effect of methyloleanolate in inducing apoptotic and autophagic cell death in cancer cells.

Materials And Methods: Flow cytometric analysis with Annexin V/PI staining, Western blot analysis, and immunofluorescence analysis were conducted in A549 and H1299 cells.

Results: Methyloleanolate increased the fraction of Annexin V/PI apoptotic cells and activated caspase-8, caspase-3, and death receptor 5 (DR5) more than oleanolate in A549 and H1299 cells pretreated with pancaspase inhibitor z-VAD-fmk and DR5 depletion. Also, methyloleanolate induced autophagic features of microtubule-associated protein light chain 3 3BII (LC3BII) conversion and puncta in A549 and H1299 cells, along with autophagosomes and vacuoles. Methyloleanolate blocked autophagy flux for impaired autophagy and chloroquine (CQ)-enhanced microtubule-associated protein LC3BII accumulation and cytotoxicity in A549 and H1299 cells, although 3-methyladenine (3-MA) did not. Interestingly, LC3BII accumulation was detected only in methyloleanolate-treated autophagy-related gene 5 () mouse embryonic fibroblast (MEF) cells but not in MEF cells. Methyloleanolate reduced p-mTOR but activated p-c-Jun N-terminal kinases and reactive oxygen species production in A549 and H1299 cells. Conversely, n-acetyl-l-cysteine and SP600125 blocked apoptotic and autophagic cascades caused by methyloleanolate in A549 and H1299 cells.

Conclusion: Overall, the findings suggest that methyloleanolate induces apoptotic and autophagic cell death in non-small cell lung cancers via reactive oxygen species generation and c-Jun N-terminal kinase phosphorylation.
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http://dx.doi.org/10.2147/OTT.S211904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815788PMC
October 2019

NEDD9 Inhibition by miR-25-5p Activation Is Critically Involved in Co-Treatment of Melatonin- and Pterostilbene-Induced Apoptosis in Colorectal Cancer Cells.

Cancers (Basel) 2019 Oct 29;11(11). Epub 2019 Oct 29.

Cancer Molecular Targeted Herbal Research Laboratory, College of Kyung Hee Medicine, Kyung Hee University, Seoul 02447, Korea.

The underlying interaction between melatonin (MLT) and daily fruit intake still remains unclear to date, despite multibiological effects of MLT. Herein, the apoptotic mechanism by co-treatment of MLT and pterostilbene (Ptero) contained mainly in grape and blueberries was elucidated in colorectal cancers (CRCs). MLT and Ptero co-treatment (MLT+Ptero) showed synergistic cytotoxicity compared with MLT or Ptero alone, reduced the number of colonies and Ki67 expression, and also increased terminal deoxynucleotidyl transferase dUTP nick end labeling- (TUNEL) positive cells and reactive oxygen species (ROS) production in CRCs. Consistently, MLT+Ptero cleaved caspase 3 and poly (ADP-ribose) polymerase (PARP), activated sex-determining region Y-Box10 (SOX10), and also attenuated the expression of Bcl-xL, neural precursor cell expressed developmentally downregulated protein 9 (NEDD9), and SOX9 in CRCs. Additionally, MLT+Ptero induced differentially expressed microRNAs (upregulation: miR-25-5p, miR-542-5p, miR-711, miR-4725-3p, and miR-4484; downregulation: miR-4504, miR-668-3p, miR-3121-5p, miR-195-3p, and miR-5194) in HT29 cells. Consistently, MLT +Ptero upregulated miR-25-5p at mRNA level and conversely NEDD9 overexpression or miR-25-5p inhibitor reversed the ability of MLT+Ptero to increase cytotoxicity, suppress colony formation, and cleave PARP in CRCs. Furthermore, immunofluorescence confirmed miR-25-5p inhibitor reversed the reduced fluorescence of NEDD9 and increased SOX10 by MLT+Ptero in HT29 cells. Taken together, our findings provided evidence that MLT+Ptero enhances apoptosis via miR-25-5p mediated NEDD9 inhibition in colon cancer cells as a potent strategy for colorectal cancer therapy.
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http://dx.doi.org/10.3390/cancers11111684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895813PMC
October 2019

Dietary Compounds for Targeting Prostate Cancer.

Nutrients 2019 Oct 8;11(10). Epub 2019 Oct 8.

College of Korean Medicine, Kyung Hee University, Seoul 02453, Korea.

Prostate cancer is the third most common cancer worldwide, and the burden of the disease is increased. Although several chemotherapies have been used, concerns about the side effects have been raised, and development of alternative therapy is inevitable. The purpose of this study is to prove the efficacy of dietary substances as a source of anti-tumor drugs by identifying their carcinostatic activities in specific pathological mechanisms. According to numerous studies, dietary substances were effective through following five mechanisms; apoptosis, anti-angiogenesis, anti-metastasis, microRNA (miRNA) regulation, and anti-multi-drug-resistance (MDR). About seventy dietary substances showed the anti-prostate cancer activities. Most of the substances induced the apoptosis, especially acting on the mechanism of caspase and poly adenosine diphosphate ribose polymerase (PARP) cleavage. These findings support that dietary compounds have potential to be used as anticancer agents as both food supplements and direct clinical drugs.
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http://dx.doi.org/10.3390/nu11102401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6835786PMC
October 2019

RNA-binding motif protein 10 induces apoptosis and suppresses proliferation by activating p53.

Oncogene 2020 01 7;39(5):1031-1040. Epub 2019 Oct 7.

Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, Louisiana, 70112, USA.

RNA-binding motif protein 10 (RBM10) is an RNA-binding protein frequently deleted or mutated in lung cancer cells. Recent reports showed that the knockdown of RBM10 in human cancer cells enhances the growth of mouse tumor xenografts, suggesting that RBM10 acts as a tumor suppressor. RBM10 also regulates alternative splicing and controls cancer cell proliferation. However, the underlying molecular mechanisms for its tumor suppression role remain largely unclear. Here, we for the first time report that RBM10 can induce apoptosis and inhibit cancer cell proliferation by activating p53. Our analysis of cancer genomic databases showed that patients with wild-type RBM10 and p53 survive longer than do those with mutated p53 or less RBM10. RBM10 overexpression markedly inhibited mitochondrial respiration, cell migration and proliferation of various cancer cells that harbor wild-type p53. Also, RBM10 overexpression elongated p53's half-life by disrupting MDM2-p53 interaction and subsequently repressing p53 ubiquitination, whereas knockdown of RBM10 decreased p53 stability. Altogether, our results demonstrate that RBM10 inhibits cancer cell proliferation and induces apoptosis in part by blocking the MDM2-p53 feedback loop.
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http://dx.doi.org/10.1038/s41388-019-1034-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994357PMC
January 2020

CNOT2 Is Critically Involved in Atorvastatin Induced Apoptotic and Autophagic Cell Death in Non-Small Cell Lung Cancers.

Cancers (Basel) 2019 Sep 30;11(10). Epub 2019 Sep 30.

College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea.

Though Atorvastatin has been used as a hypolipidemic agent, its anticancer mechanisms for repurposing are not fully understood so far. Thus, in the current study, its apoptotic and autophagic mechanisms were investigated in non-small cell lung cancers (NSCLCs). Atorvastatin increased cytotoxicity, sub G1 population, the number of apoptotic bodies, cleaved poly (ADP-ribose) polymerase (PARP) and caspase 3 and activated p53 in H1299, H596, and H460 cells. Notably, Atorvastatin inhibited the expression of c-Myc and induced ribosomal protein L5 and L11, but depletion of L5 reduced PARP cleavages induced by Atorvastatin rather than L11 in H1299 cells. Also, Atorvastatin increased autophagy microtubule-associated protein 1A/1B-light chain 3II (LC3 II) conversion, p62/sequestosome 1 (SQSTM1) accumulation with increased number of LC3II puncta in H1299 cells. However, late stage autophagy inhibitor chloroquine (CQ) increased cytotoxicity in Atorvastatin treated H1299 cells compared to early stage autophagy inhibitor 3-methyladenine (3-MA). Furthermore, autophagic flux assay using RFP-GFP-LC3 constructs and Lysotracker Red or acridine orange-staining demonstrated that autophagosome-lysosome fusion is blocked by Atorvastatin treatment in H1299 cells. Conversely, overexpression of CCR4-NOT transcription complex subunit 2(CNOT2) weakly reversed the ability of Atorvastatin to increase cytotoxicity, sub G1 population, cleavages of PARP and caspase 3, LC3II conversion and p62/SQSTM1 accumulation in H1299 cells. In contrast, CNOT2 depletion enhanced cleavages of PARP and caspase 3, LC3 conversion and p62/SQSTM1 accumulation in Atorvastatin treated H1299 cells. Overall, these findings suggest that CNOT2 signaling is critically involved in Atorvastatin induced apoptotic and autophagic cell death in NSCLCs.
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http://dx.doi.org/10.3390/cancers11101470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826547PMC
September 2019

Erratum to "Melatonin Suppresses the Expression of 45S Preribosomal RNA and Upstream Binding Factor and Enhances the Antitumor Activity of Puromycin in MDA-MB-231 Breast Cancer Cells".

Evid Based Complement Alternat Med 2019;2019:5741476. Epub 2019 Jul 21.

College of Oriental Medicine, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Republic of Korea.

[This corrects the article DOI: 10.1155/2013/879746.].
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http://dx.doi.org/10.1155/2019/5741476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679860PMC
July 2019

Antitumor Effect of Pyrogallol via miR-134 Mediated S Phase Arrest and Inhibition of PI3K/AKT/Skp2/cMyc Signaling in Hepatocellular Carcinoma.

Int J Mol Sci 2019 Aug 16;20(16). Epub 2019 Aug 16.

College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea.

Though Pyrogallol, one of the natural polyphenols, was known to have anti-inflammatory and antitumor effects in breast and colon cancers, the underlying antitumor mechanisms of Pyrogallol, still remain unclear so far. Here, the antitumor mechanisms of Pyrogallol were elucidated in Hep3B and Huh7 hepatocellular carcinoma cells (HCCs). Pyrogallol showed significant cytotoxicity and reduced the number of colonies in Hep3B and Huh7 cells. Interestingly, Pyrogallol induced S-phase arrest and attenuated the protein expression of CyclinD1, Cyclin E, Cyclin A, c-Myc, S-phase kinase-associated protein 2 (Skp2), p-AKT, PI3K, increased the protein expression of p27, and also reduced the fluorescent expression of Cyclin E in Hep3B and Huh7 cells. Furthermore, Pyrogallol disturbed the interaction between Skp2, p27, and c-Myc in Huh7 cells. Notably, Pyrogallol upregulated miRNA levels of miR-134, and conversely, miR-134 inhibition rescued the decreased expression levels of c-Myc, Cyclin E, and Cyclin D1 and increased the expression of p27 by Pyrogallol in Huh7 cells. Taken together, our findings provide insight that Pyrogallol exerts antitumor effects in HCCs via miR-134 activation-mediated S-phase arrest and inhibition of PI3K/AKT/Skp2/cMyc signaling as a potent anticancer candidate.
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http://dx.doi.org/10.3390/ijms20163985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6720540PMC
August 2019
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