Publications by authors named "Misun Won"

67 Publications

DGG-100629 inhibits lung cancer growth by suppressing the NFATc1/DDIAS/STAT3 pathway.

Exp Mol Med 2021 Apr 15;53(4):643-653. Epub 2021 Apr 15.

Personalized Genomic Medicine Research Center, KRIBB, Daejeon, 34141, Korea.

DNA damage-induced apoptosis suppressor (DDIAS) promotes the progression of lung cancer and hepatocellular carcinoma through the regulation of multiple pathways. We screened a chemical library for anticancer agent(s) capable of inhibiting DDIAS transcription. DGG-100629 was found to suppress lung cancer cell growth through the inhibition of DDIAS expression. DGG-100629 induced c-Jun NH(2)-terminal kinase (JNK) activation and inhibited NFATc1 nuclear translocation. Treatment with SP600125 (a JNK inhibitor) or knockdown of JNK1 restored DDIAS expression and reversed DGG-100629-induced cell death. In addition, DGG-100629 suppressed the signal transducer and activator of transcription (STAT3) signaling pathway. DDIAS or STAT3 overexpression restored lung cancer cell growth in the presence of DGG-100629. In a xenograft assay, DGG-100629 inhibited tumor growth by reducing the level of phosphorylated STAT3 and the expression of STAT3 target genes. Moreover, DGG-100629 inhibited the growth of lung cancer patient-derived gefitinib-resistant cells expressing NFATc1 and DDIAS. Our findings emphasize the potential of DDIAS blockade as a therapeutic approach and suggest a novel strategy for the treatment of gefitinib-resistant lung cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s12276-021-00601-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102629PMC
April 2021

The disubstituted adamantyl derivative LW1564 inhibits the growth of cancer cells by targeting mitochondrial respiration and reducing hypoxia-inducible factor (HIF)-1α accumulation.

Exp Mol Med 2020 11 25;52(11):1845-1856. Epub 2020 Nov 25.

College of Pharmacy, Dongguk University-Seoul, Goyang, 10326, Korea.

Targeting cancer metabolism has emerged as an important cancer therapeutic strategy. Here, we describe the synthesis and biological evaluation of a novel class of hypoxia-inducible factor (HIF)-1α inhibitors, disubstituted adamantyl derivatives. One such compound, LW1564, significantly suppressed HIF-1α accumulation and inhibited the growth of various cancer cell lines, including HepG2, A549, and HCT116. Measurements of the oxygen consumption rate (OCR) and ATP production rate revealed that LW1564 suppressed mitochondrial respiration, thereby increasing the intracellular oxygen concentration to stimulate HIF-1α degradation. LW1564 also significantly decreased overall ATP levels by inhibiting mitochondrial electron transport chain (ETC) complex I and downregulated mammalian target of rapamycin (mTOR) signaling by increasing the AMP/ATP ratio, which increased AMP-activated protein kinase (AMPK) phosphorylation. Consequently, LW1564 promoted the phosphorylation of acetyl-CoA carboxylase, which inhibited lipid synthesis. In addition, LW1564 significantly inhibited tumor growth in a HepG2 mouse xenograft model. Taken together, the results indicate that LW1564 inhibits the growth of cancer cells by targeting mitochondrial ETC complex I and impairing cancer cell metabolism. We, therefore, suggest that LW1564 may be a potent therapeutic agent for a subset of cancers that rely on oxidative phosphorylation for ATP generation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s12276-020-00523-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080809PMC
November 2020

VGLL1 phosphorylation and activation promotes gastric cancer malignancy via TGF-β/ERK/RSK2 signaling.

Biochim Biophys Acta Mol Cell Res 2021 01 16;1868(1):118892. Epub 2020 Oct 16.

Personalized Genomic Medicine Research Center, KRIBB, Daejeon, 34141, Republic of Korea; KRIBB School of Bioscience, University of Science and Technology, Daejeon, 34113, Republic of Korea; R&D Center, OneCureGEN Co., Ltd, Daejeon, 34141, Republic of Korea,. Electronic address:

We previously reported that vestigial-like 1 (VGLL1), a cofactor of transcriptional enhanced associate domain 4 (TEAD4), is transcriptionally regulated by PI3K and β-catenin signaling and is involved in gastric cancer malignancy. However, the precise mechanism underlying the regulation of VGLL1 activation remains unknown. Therefore, we aimed to investigate the molecular mechanism underlying the transforming growth factor-β (TGF-β)-mediated activation of VGLL1 and the VGLL1-TEAD4 interaction in gastric cancer cells. We showed that TGF-β enhanced VGLL1 phosphorylation and that this phosphorylated VGLL1 functioned as a transcription cofactor of TEAD4 in NUGC3 cells. TGF-β also increased the phosphorylation of ERK and ribosomal S6 kinase 2 (RSK2) in NUGC3 cells, thereby triggering the translocation of phosphorylated RSK2 to the nucleus. Site-directed mutagenesis and immunoprecipitation experiments revealed that RSK2 phosphorylated VGLL1 at S84 in the presence of TGF-β. Mutation of VGLL1 at S84 suppressed VGLL1-TEAD4 binding and the subsequent transcriptional activation of matrix metalloprotease 9 (MMP9). Moreover, VGLL1 peptide containing S84 suppressed the TGF-β-induced MMP9 expression and reduced the invasion and proliferation of gastric cancer cells, whereas VGLL1 peptide containing S84A did not. Furthermore, suppression of expression or activation of VGLL1 enhances the therapeutic effects of lapatinib. Collectively, these results indicate that VGLL1 phosphorylation via TGF-β/ERK/RSK2 signaling plays a crucial role in MMP9-mediated malignancy of gastric cancer. In addition, our study highlights the therapeutic potential of the peptide containing VGLL1 S84 for the treatment of gastric cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbamcr.2020.118892DOI Listing
January 2021

Miconazole inhibits signal transducer and activator of transcription 3 signaling by preventing its interaction with DNA damage-induced apoptosis suppressor.

Cancer Sci 2020 Jul 31;111(7):2499-2507. Epub 2020 May 31.

Personalized Genomic Medicine Research Center, KRIBB, Daejeon, Korea.

DNA damage-induced apoptosis suppressor (DDIAS) facilitates the survival of lung cancer by suppressing apoptosis. Moreover, DDIAS promotes tyrosine phosphorylation of signal transducer and activator of transcription 3 (STAT3) via their interaction. Here, we identified miconazole as an inhibitor of DDIAS/STAT3 interaction by screening a chemical library using a yeast two-hybrid assay. Miconazole inhibited growth, migration and invasion of lung cancer cells. Furthermore, miconazole suppressed STAT3 tyrosine Y705 phosphorylation and the expression of its target genes, such as cyclin D1, survivin and snail but had no suppressive effect on the activation of ERK1/2 or AKT, which is involved in the survival of lung cancer. As expected, no interaction between DDIAS and STAT3 occurred in the presence of miconazole, as confirmed by immunoprecipitation assays. Mouse xenograft experiments showed that miconazole significantly suppressed both tumor size and weight in an NCI-H1703 mouse model. Tyrosine phosphorylation of STAT3 at Y705 and expression of its targets, such as cyclin D1, survivin and snail, were decreased in miconazole-treated tumor tissues, as compared with those in vehicle-treated tumor tissues. These data suggest that miconazole exerts an anti-cancer effect by suppressing STAT3 activation through inhibiting DDIAS/STAT3 binding.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cas.14432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385363PMC
July 2020

DDIAS promotes STAT3 activation by preventing STAT3 recruitment to PTPRM in lung cancer cells.

Oncogenesis 2020 Jan 2;9(1). Epub 2020 Jan 2.

Personalized Genomic Medicine Research Center, KRIBB, Daejeon, 34141, Korea.

DNA damage-induced apoptosis suppressor (DDIAS) regulates cancer cell survival. Here we investigated the involvement of DDIAS in IL-6-mediated signaling to understand the mechanism underlying the role of DDIAS in lung cancer malignancy. We showed that DDIAS promotes tyrosine phosphorylation of signal transducer and activator of transcription 3 (STAT3), which is constitutively activated in malignant cancers. Interestingly, siRNA protein tyrosine phosphatase (PTP) library screening revealed protein tyrosine phosphatase receptor mu (PTPRM) as a novel STAT3 PTP. PTPRM knockdown rescued the DDIAS-knockdown-mediated decrease in STAT3 Y705 phosphorylation in the presence of IL-6. However, PTPRM overexpression decreased STAT3 Y705 phosphorylation. Moreover, endogenous PTPRM interacted with endogenous STAT3 for dephosphorylation at Y705 following IL-6 treatment. As expected, PTPRM bound to wild-type STAT3 but not the STAT3 Y705F mutant. PTPRM dephosphorylated STAT3 in the absence of DDIAS, suggesting that DDIAS hampers PTPRM/STAT3 interaction. In fact, DDIAS bound to the STAT3 transactivation domain (TAD), which competes with PTPRM to recruit STAT3 for dephosphorylation. Thus we show that DDIAS prevents PTPRM/STAT3 binding and blocks STAT3 Y705 dephosphorylation, thereby sustaining STAT3 activation in lung cancer. DDIAS expression strongly correlates with STAT3 phosphorylation in human lung cancer cell lines and tissues. Thus DDIAS may be considered as a potential biomarker and therapeutic target in malignant lung cancer cells with aberrant STAT3 activation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41389-019-0187-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949220PMC
January 2020

PI3K/AKT/β-Catenin Signaling Regulates Vestigial-Like 1 Which Predicts Poor Prognosis and Enhances Malignant Phenotype in Gastric Cancer.

Cancers (Basel) 2019 Dec 3;11(12). Epub 2019 Dec 3.

Personalized Genomic Medicine Research Center, KRIBB, Daejeon 34141, Korea.

Although gastric cancer is a common cause of cancer mortality worldwide, its biological heterogeneity limits the available therapeutic options. Therefore, identifying novel therapeutic targets for developing effective targeted therapy of gastric cancer is a pressing need. Here, we investigate molecular function and regulatory mechanisms of () in gastric cancer. Microarray analysis of 556 gastric cancer tissues revealed that VGLL1 was a prognostic biomarker that correlated with PI3KCA and PI3KCB. regulates the proliferation of gastric cancer cells, as shown in live cell imaging, sphere formation, and in vivo xenograft model. Tail vein injection of NUGC3 cells expressing sh resulted in less lung metastasis occurring when compared to the control. In contrast, larger metastatic lesions in lung and liver were detected in the -overexpressing NUGC3 cell xenograft excision mouse model. Importantly, expression is transcriptionally regulated by the PI3K-AKT-β-catenin pathway. Subsequently, MMP9, a key molecule in gastric cancer, was explored as one of target genes that were transcribed by VGLL1-TEAD4 complex, a component of the transcription factor. Taken together, PI3K/AKT/β-catenin signaling regulates the transcription of , which promotes the proliferation and metastasis in gastric cancer. This finding suggests VGLL1 as a novel prognostic biomarker and a potential therapeutic target.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers11121923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966677PMC
December 2019

Bcl-2-dependent synthetic lethal interaction of the IDF-11774 with the V0 subunit C of vacuolar ATPase (ATP6V0C) in colorectal cancer.

Br J Cancer 2018 11 13;119(11):1347-1357. Epub 2018 Nov 13.

Personalized Genomic Medicine Research Center, KRIBB, Daejeon, 34141, Korea.

Background: The IDF-11774, a novel clinical candidate for cancer therapy, targets HSP70 and inhibits mitochondrial respiration, resulting in the activation of AMPK and reduction in HIF-1α accumulation.

Methods: To identify genes that have synthetic lethality to IDF-11774, RNA interference screening was conducted, using pooled lentiviruses expressing a short hairpin RNA library.

Results: We identified ATP6V0C, encoding the V0 subunit C of lysosomal V-ATPase, knockdown of which induced a synergistic growth-inhibitory effect in HCT116 cells in the presence of IDF-11774. The synthetic lethality of IDF-11774 with ATP6V0C possibly correlates with IDF-11774-mediated autolysosome formation. Notably, the synergistic effect of IDF-11774 and the ATP6V0C inhibitor, bafilomycin A1, depended on the PIK3CA genetic status and Bcl-2 expression, which regulates autolysosome formation and apoptosis. Similarly, in an experiment using conditionally reprogramed cells derived from colorectal cancer patients, synergistic growth inhibition was observed in cells with low Bcl-2 expression.

Conclusions: Bcl-2 is a biomarker for the synthetic lethal interaction of IDF-11774 with ATP6V0C, which is clinically applicable for the treatment of cancer patients with IDF-11774 or autophagy-inducing anti-cancer drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41416-018-0289-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6265273PMC
November 2018

RNF25 promotes gefitinib resistance in EGFR-mutant NSCLC cells by inducing NF-κB-mediated ERK reactivation.

Cell Death Dis 2018 05 22;9(6):587. Epub 2018 May 22.

Personal Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, South Korea.

Non-small cell lung cancer (NSCLC) patients with EGFR mutations initially respond well to EGFR tyrosine kinase inhibitors (TKIs) but eventually exhibit acquired or innate resistance to the therapies typically due to gene mutations, such as EGFR T790M mutation or a second mutation in the downstream pathways of EGFR. Importantly, a significant portion of NSCLC patients shows TKI resistance without any known mechanisms, calling more comprehensive studies to reveal the underlying mechanisms. Here, we investigated a synthetic lethality with gefitinib using a genome-wide RNAi screen in TKI-resistant EGFR-mutant NSCLC cells, and identified RNF25 as a novel factor related to gefitinib resistance. Depletion of RNF25 expression substantially sensitized NSCLC cells to gefitinib treatment, while forced expression of RNF25 augmented gefitinib resistance in sensitive cells. We demonstrated that RNF25 mediates NF-κB activation in gefitinib-treated cells, which, in turn, induces reactivation of ERK signal to cause the drug resistance. We identified that the ERK reactivation occurs via the function of cytokines, such as IL-6, whose expression is transcriptionally induced in a gefitinib-dependent manner by RNF25-mediated NF-κB signals. These results suggest that RNF25 plays an essential role in gefitinib resistance of NSCLC by mediating cross-talk between NF-κB and ERK pathways, and provide a novel target for the combination therapy to overcome TKI resistance of NSCLC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41419-018-0651-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964247PMC
May 2018

DDIAS suppresses TRAIL-mediated apoptosis by inhibiting DISC formation and destabilizing caspase-8 in cancer cells.

Oncogene 2018 03 15;37(9):1251-1262. Epub 2017 Dec 15.

Personalized Genomic Medicine Research Center, KRIBB, Daejeon, Korea.

DNA damage-induced apoptosis suppressor (DDIAS) has an anti-apoptotic function during DNA damage in lung cancer. However, the anti-apoptotic mechanism of DDIAS in cancer cells under other conditions has not been reported. We report here that DDIAS protects cancer cells from tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by two distinct mechanisms in non-small cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC) cells. DDIAS depletion sensitized NSCLC and HCC cells to TRAIL-mediated apoptosis, an effect that was abrogated by pharmacological or genetic inhibition of caspase-8 and was independent of caspase-9, p53, or mitogen-activated protein kinase signaling. Interestingly, we found that the N terminus of DDIAS interacted with the death effector domain of Fas-associated protein death domain (FADD) and prevented its recruitment to the death-inducing signaling complex (DISC), thereby blocking caspase-8 activation. DDIAS knockdown also suppressed epidermal growth factor-induced phosphorylation of p90 ribosomal S6 kinase (RSK) 2 and stabilized caspase-8 by preventing its ubiquitination and proteasomal degradation. This effect was abolished by RSK2 overexpression. Taken together, DDIAS has dual functions in inhibiting DISC formation as well as in destabilizing caspase-8, thereby suppressing TRAIL-mediated apoptosis of cancer cells. Thus, we suggest that DDIAS can serve as an effective therapeutic target in the treatment of NSCLC and HCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41388-017-0025-yDOI Listing
March 2018

Methyl 3-(3-(4-(2,4,4-Trimethylpentan-2-yl)phenoxy)-propanamido)benzoate as a Novel and Dual Malate Dehydrogenase (MDH) 1/2 Inhibitor Targeting Cancer Metabolism.

J Med Chem 2017 10 16;60(20):8631-8646. Epub 2017 Oct 16.

College of Pharmacy, Dongguk University , Goyang 10326, Korea.

Previously, we reported a hypoxia-inducible factor (HIF)-1 inhibitor LW6 containing an (aryloxyacetylamino)benzoic acid moiety inhibits malate dehydrogenase 2 (MDH2) using a chemical biology approach. Structure-activity relationship studies on a series of (aryloxyacetylamino)benzoic acids identified selective MDH1, MDH2, and dual inhibitors, which were used to study the relationship between MDH enzyme activity and HIF-1 inhibition. We hypothesized that dual inhibition of MDH1 and MDH2 might be a powerful approach to target cancer metabolism and selected methyl-3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)-benzoate (16c) as the most potent dual inhibitor. Kinetic studies revealed that compound 16c competitively inhibited MDH1 and MDH2. Compound 16c inhibited mitochondrial respiration and hypoxia-induced HIF-1α accumulation. In xenograft assays using HCT116 cells, compound 16c demonstrated significant in vivo antitumor efficacy. This finding provides concrete evidence that inhibition of both MDH1 and MDH2 may provide a valuable platform for developing novel therapeutics that target cancer metabolism and tumor growth.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.7b01231DOI Listing
October 2017

Elasticity-based development of functionally enhanced multicellular 3D liver encapsulated in hybrid hydrogel.

Acta Biomater 2017 12 28;64:67-79. Epub 2017 Sep 28.

Biomedical Translational Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea; Functional Genomics, Korea University of Science and Technology (UST), Daejeon 34141, Republic of Korea. Electronic address:

Current in vitro liver models provide three-dimensional (3-D) microenvironments in combination with tissue engineering technology and can perform more accurate in vivo mimicry than two-dimensional models. However, a human cell-based, functionally mature liver model is still desired, which would provide an alternative to animal experiments and resolve low-prediction issues on species differences. Here, we prepared hybrid hydrogels of varying elasticity and compared them with a normal liver, to develop a more mature liver model that preserves liver properties in vitro. We encapsulated HepaRG cells, either alone or with supporting cells, in a biodegradable hybrid hydrogel. The elastic modulus of the 3D liver dynamically changed during culture due to the combined effects of prolonged degradation of hydrogel and extracellular matrix formation provided by the supporting cells. As a result, when the elastic modulus of the 3D liver model converges close to that of the in vivo liver (≅ 2.3 to 5.9 kPa), both phenotypic and functional maturation of the 3D liver were realized, while hepatic gene expression, albumin secretion, cytochrome p450-3A4 activity, and drug metabolism were enhanced. Finally, the 3D liver model was expanded to applications with embryonic stem cell-derived hepatocytes and primary human hepatocytes, and it supported prolonged hepatocyte survival and functionality in long-term culture. Our model represents critical progress in developing a biomimetic liver system to simulate liver tissue remodeling, and provides a versatile platform in drug development and disease modeling, ranging from physiology to pathology.

Statement Of Significance: We provide a functionally improved 3D liver model that recapitulates in vivo liver stiffness. We have experimentally addressed the issues of orchestrated effects of mechanical compliance, controlled matrix formation by stromal cells in conjunction with hepatic differentiation, and functional maturation of hepatocytes in a dynamic 3D microenvironment. Our model represents critical progress in developing a biomimetic liver system to simulate liver tissue remodeling, and provides a versatile platform in drug development and disease modeling, ranging from physiology to pathology. Additionally, recent advances in the stem-cell technologies have made the development of 3D organoid possible, and thus, our study also provides further contribution to the development of physiologically relevant stem-cell-based 3D tissues that provide an elasticity-based predefined biomimetic 3D microenvironment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.actbio.2017.09.041DOI Listing
December 2017

The novel hypoxia-inducible factor-1α inhibitor IDF-11774 regulates cancer metabolism, thereby suppressing tumor growth.

Cell Death Dis 2017 06 1;8(6):e2843. Epub 2017 Jun 1.

Personalized Genomic Medicine Research Center, KRIBB, Daejeon 305-806, Korea.

HIF-1 is associated with poor prognoses and therapeutic resistance in cancer patients. We previously developed a novel hypoxia-inducible factor (HIF)-1 inhibitor, IDF-11774, a clinical candidate for cancer therapy. We also reported that IDF-1174 inhibited HSP70 chaperone activity and suppressed accumulation of HIF-1α. In this study, IDF-11774 inhibited the accumulation of HIF-1α in vitro and in vivo in colorectal carcinoma HCT116 cells under hypoxic conditions. Moreover, IDF-11774 treatment suppressed angiogenesis of cancer cells by reducing the expression of HIF-1 target genes, reduced glucose uptake, thereby sensitizing cells to growth under low glucose conditions, and decreased the extracellular acidification rate (ECAR) and oxygen consumption rate of cancer cells. Metabolic profiling of IDF-11774-treated cells revealed low levels of NAD, NADP, and lactate, as well as of intermediates in glycolysis and the tricarboxylic acid cycle. In addition, we observed elevated AMP and diminished ATP levels, resulting in a high AMP/ATP ratio. The level of AMP-activated protein kinase phosphorylation also increased, leading to inhibition of mTOR signaling in treated cells. In vivo xenograft assays demonstrated that IDF-11774 exhibited substantial anticancer efficacy in mouse models containing KRAS, PTEN, or VHL mutations, which often occur in malignant cancers. Collectively, our data indicate that IDF-11774 suppressed hypoxia-induced HIF-1α accumulation and repressed tumor growth by targeting energy production-related cancer metabolism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/cddis.2017.235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520894PMC
June 2017

Synthesis and biological evaluation of kresoxim-methyl analogues as novel inhibitors of hypoxia-inducible factor (HIF)-1 accumulation in cancer cells.

Bioorg Med Chem Lett 2017 07 9;27(13):3026-3029. Epub 2017 May 9.

School of Chemistry and Biochemistry, Yeungnam University, 280 Daehak-Ro, Gyeongsan-si, Gyeongbuk 38541, Republic of Korea. Electronic address:

We designed and synthesized strobilurin analogues as hypoxia-inducible factor (HIF) inhibitors based on the molecular structure of kresoxim-methyl. Biological evaluation in human colorectal cancer HCT116 cells showed that most of the synthesized kresoxim-methyl analogues possessed moderate to potent inhibitory activity against hypoxia-induced HIF-1 transcriptional activation. Three candidates, compounds 11b, 11c, and 11d were identified as potent inhibitors against HIF-1 activation with IC values of 0.60-0.94µM. Under hypoxic condition, compounds 11b, 11c, and 11d increased the intracellular oxygen contents, thereby attenuating the hypoxia-induced accumulation of HIF-1α protein.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2017.05.024DOI Listing
July 2017

Stability of the cancer target DDIAS is regulated by the CHIP/HSP70 pathway in lung cancer cells.

Cell Death Dis 2017 01 12;8(1):e2554. Epub 2017 Jan 12.

Personalized Genomic Medicine Research Center, KRIBB, Daejeon 305-806, Korea.

DNA damage-induced apoptosis suppressor (DDIAS) rescues lung cancer cells from apoptosis in response to DNA damage. DDIAS is transcriptionally activated by NFATc1 and EGF-mediated ERK5/MEF2B, leading to cisplatin resistance and cell invasion. Therefore, DDIAS is suggested as a therapeutic target for lung cancer. Here, we report that DDIAS stability is regulated by E3 U-box ubiquitin ligase carboxyl terminus of HSP70-interacting protein (CHIP)-mediated proteasomal degradation. We first isolated CHIP as an interacting partner of DDIAS by yeast two-hybrid screening. CHIP physically associated with both the N- and C-terminal regions of DDIAS, targeting it for proteasomal degradation and reducing the DDIAS half-life. CHIP overexpression analyses indicated that the tetratrico peptide repeat (TPR) domain and the U-box are required for DDIAS ubiquitination. It is likely that HSP70-bound DDIAS is recruited to the CHIP E3 ligase via the TPR domain, suggesting DDIAS as a client protein of HSP70. In addition, CHIP overexpression in lung cancer cells expressing high DDIAS levels induced significant growth inhibition by enhancing DDIAS degradation. Furthermore, simultaneous CHIP overexpression and DNA damage agent treatment caused a substantial increase in the apoptosis of lung cancer cells. Taken together, these findings indicate that the stability of the DDIAS protein is regulated by CHIP/HSP70-mediated proteasomal degradation and that CHIP overexpression stimulates the apoptosis of lung cancer cells in response to DNA-damaging agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/cddis.2016.488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386388PMC
January 2017

DNA damage induced apoptosis suppressor (DDIAS) is upregulated via ERK5/MEF2B signaling and promotes β-catenin-mediated invasion.

Biochim Biophys Acta 2016 11 10;1859(11):1449-1458. Epub 2016 Jul 10.

Genomic Personalized Medicine Research Center, KRIBB, Daejeon 305-806, Republic of Korea; Functional Genomics, University of Science and Technology, Daejeon 305-701, Republic of Korea. Electronic address:

DNA damage induced apoptosis suppressor (DDIAS) is an anti-apoptotic protein that promotes cancer cell survival. We previously reported that DDIAS is transcriptionally activated by nuclear factor of activated T cells 2 (NFATc1). However, the upstream regulation of DDIAS expression by growth factors has not been studied. Here, we demonstrate that DDIAS expression is induced by extracellular signal-regulated kinase 5 (ERK5) and myocyte enhancer factor 2B (MEF2B) in response to epidermal growth factor (EGF) and that it positively regulates β-catenin signaling in HeLa cells. The genetic or pharmacological inhibition of ERK5 suppressed DDIAS induction following EGF exposure and the overexpression of constitutively active MEK5 (CA-MEK5) enhanced DDIAS expression. In chromatin immunoprecipitation assays, MEF2B, a downstream target of ERK5, exhibited sequence-specific binding to a MEF2 binding site in the DDIAS promoter following treatment with EGF. The overexpression of MEF2B increased the EGF-mediated induction of DDIAS expression, whereas the knockdown of MEF2B impaired this effect. Furthermore, DDIAS promoted invasion by increasing β-catenin expression at the post-translational level in response to EGF, suggesting that DDIAS plays a crucial role in the metastasis of cancer cells by regulating β-catenin expression. It is unlikely that MEF2B and NFATc1 cooperatively regulate DDIAS transcription in response to EGF. Collectively, EGF activates the ERK5/MEF2 pathway, which in turn induces DDIAS expression to promote cancer cell invasion by activating β-catenin target genes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbagrm.2016.07.003DOI Listing
November 2016

Data on the transcriptional regulation of DNA damage induced apoptosis suppressor (DDIAS) by ERK5/MEF2B pathway in lung cancer cells.

Data Brief 2016 Dec 6;9:257-61. Epub 2016 Sep 6.

Personalized Genomic Medicine Research Center, KRIBB, Daejeon 305-806, Korea; Functional Genomics, University of Science and Technology, Daejeon 305-701, Korea.

The data included in this article are associated with the article entitled "DNA-damage-induced apoptosis suppressor (DDIAS) is upregulated via ERK5/MEF2B signaling and promotes β-catenin-mediated invasion" (J.Y. Im, S.H. Yoon, B.K. Kim, H.S. Ban, K.J. Won, K.S. Chung, K.E. Jung, M. Won) [1]. Quantitative RT-PCR data revealed that genetic or pharmacological inhibition of extracellular signal-regulated kinase 5 (ERK5) suppresses DDIAS transcription in response to epidermal growth factor (EGF) in Hela cells. p300 did not interact with myocyte enhancer factor 2B (MEF2B), a downstream target of ERK5 and affect transcription of DDIAS. Moreover, DDIAS transcription is activated by ERK5/MEF2B signaling on EGF exposure in the non-small cell lung cancer cells (NSCLC) NCI-H1703 and NCI-H1299. DDIAS knockdown suppresses lung cancer cell invasion by decreasing β-catenin protein level on EGF exposure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.dib.2016.08.066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5021921PMC
December 2016

A Novel Malate Dehydrogenase 2 Inhibitor Suppresses Hypoxia-Inducible Factor-1 by Regulating Mitochondrial Respiration.

PLoS One 2016 9;11(9):e0162568. Epub 2016 Sep 9.

Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.

We previously reported that hypoxia-inducible factor (HIF)-1 inhibitor LW6, an aryloxyacetylamino benzoic acid derivative, inhibits malate dehydrogenase 2 (MDH2) activity during the mitochondrial tricarboxylic acid (TCA) cycle. In this study, we present a novel MDH2 inhibitor compound 7 containing benzohydrazide moiety, which was identified through structure-based virtual screening of chemical library. Similar to LW6, compound 7 inhibited MDH2 activity in a competitive fashion, thereby reducing NADH level. Consequently, compound 7 reduced oxygen consumption and ATP production during the mitochondrial respiration cycle, resulting in increased intracellular oxygen concentration. Therefore, compound 7 suppressed the accumulation of HIF-1α and expression of its target genes, vascular endothelial growth factor (VEGF) and glucose transporter 1 (GLUT1). Moreover, reduction in ATP content activated AMPK, thereby inactivating ACC and mTOR the downstream pathways. As expected, compound 7 exhibited significant growth inhibition of human colorectal cancer HCT116 cells. Compound 7 demonstrated substantial anti-tumor efficacy in an in vivo xenograft assay using HCT116 mouse model. Taken together, a novel MDH2 inhibitor, compound 7, suppressed HIF-1α accumulation via reduction of oxygen consumption and ATP production, integrating metabolism into anti-cancer efficacy in cancer cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0162568PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5017629PMC
August 2017

Shikonin induces apoptosis of lung cancer cells via activation of FOXO3a/EGR1/SIRT1 signaling antagonized by p300.

Biochim Biophys Acta 2016 11 21;1863(11):2584-2593. Epub 2016 Jul 21.

Biomedical Translational Research Center, KRIBB, Daejeon 34141, Republic of Korea; Functional Genomics, Korea University of Science and Technology (UST), Daejeon, 305-806, Republic of Korea. Electronic address:

Shikonin derivatives exert powerful cytotoxic effects including induction of apoptosis. Here, we demonstrate the cytotoxic efficacy of shikonin in vivo in xenograft models, which did not affect body weight as well as its reduction of cell viability in vitro using several non-small cell lung cancer (NSCLC) cell lines. We found that inhibition of AKT by shikonin activated the forkhead box (FOX)O3a/early growth response protein (EGR)1 signaling cascade and enhanced the expression of the target gene Bim, leading to apoptosis in lung cancer cells. Overexpression of wild-type or a constitutively active mutant of FOXO3a enhanced shikonin-induced Bim expression. The NAD-dependent histone deacetylase sirtuin (SIRT)1 amplified the pro-apoptotic effect by deacetylating FOXO3a, which induced EGR1 binding to the Bim promoter and activated Bim expression. Meanwhile, PI3K/AKT activity was enhanced, whereas that of FOXO3a was reduced and p300 was upregulated by treatment with a sublethal dose of shikonin. FOXO3a acetylation was enhanced by p300 overexpression, while shikonin-induced Bim expression was suppressed by p300 overexpression, which promoted cell survival. FOXO3a acetylation was increased by p300 overexpression and treatment with SIRT1 inhibitor, improving cell survival. In addition, shikonin-induced FOXO3a nuclear localization was blocked by AKT activation and SIRT1 inhibition, which blocked Bim expression and conferred resistance to the cytotoxic effects of shikonin. The EGR1 increase induced by shikonin was restored by pretreatment with SIRT1 inhibitor. These results suggest that shikonin induces apoptosis in some lung cancer cells via activation of FOXO3a/EGR1/SIRT1 signaling, and that AKT and p300 negatively regulate this process via Bim upregulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbamcr.2016.07.005DOI Listing
November 2016

Identification of Targets of the HIF-1 Inhibitor IDF-11774 Using Alkyne-Conjugated Photoaffinity Probes.

Bioconjug Chem 2016 08 18;27(8):1911-20. Epub 2016 Jul 18.

College of Pharmacy, Dongguk University-Seoul , Goyang 410-820, Korea.

We developed a hypoxia-inducible factor-1 (HIF-1) inhibitor, IDF-11774, as a clinical candidate for cancer therapy. To understand the mechanism of action of IDF-11774, we attempted to isolate target proteins of IDF-11774 using bioconjugated probes. Multifunctional chemical probes containing sites for click conjugation and photoaffinity labeling were designed and synthesized. After fluorescence and photoaffinity labeling of proteins, two-dimensional electrophoresis (2DE) was performed to isolate specific molecular targets of IDF-11774. Heat shock protein (HSP) 70 was identified as a target protein of IDF-11774. We revealed that IDF-11774 inhibited HSP70 chaperone activity by binding to its allosteric pocket, rather than the ATP-binding site in its nucleotide-binding domain (NBD). Moreover, IDF-11774 reduced the oxygen consumption rate (OCR) and ATP production, thereby increasing intracellular oxygen tension. This result suggests that the inhibition of HSP70 chaperone activity by IDF-11774 suppresses HIF-1α refolding and stimulates HIF-1α degradation. Taken together, these findings indicate that IDF-11774-derived chemical probes successfully identified IDF-11774's target molecule, HSP70, and elucidated the mode of action of IDF-11774 in inhibiting HSP70 chaperone activity and stimulating HIF-1α degradation in cancer cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.bioconjchem.6b00305DOI Listing
August 2016

Hypoxia-inducible factor (HIF) inhibitors: a patent survey (2011-2015).

Expert Opin Ther Pat 2016 16;26(3):309-22. Epub 2016 Feb 16.

d Chemical Resources Laboratory , Tokyo Institute of Technology , Yokohama , Japan.

Introduction: Hypoxia-inducible factor (HIF)-1α regulates the expression of genes involved in angiogenesis, cellular energy metabolism, and cell survival during cancer development. The increased expression of HIF-1α in most solid tumors is associated with poor prognoses and therapeutic outcomes. Therefore, HIF has been recognized as an attractive target for cancer therapy, and many HIF inhibitors have been reported.

Areas Covered: This patent survey summarizes the information about patented HIF inhibitors over the last 5 years (2011-2015).

Expert Opinion: Although many of the HIF inhibitors reviewed in this patent survey possess inhibitory activity against cancer and HIF-related diseases, the compounds are still in the early stages of development, most likely due to the complexity of the HIF-1 pathway and their different mechanisms of action for HIF inhibition. Most cancer cells use the glycolytic pathway for energy production and HIF-1α participates deeply in the expression of several glycolytic enzymes. Therefore, a detailed study of HIF's function in cancer metabolisms may provide us an alternative strategy for further development of HIF inhibitors in cancer therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1517/13543776.2016.1146252DOI Listing
October 2016

NFATc1 regulates the transcription of DNA damage-induced apoptosis suppressor.

Data Brief 2015 Dec 17;5:975-80. Epub 2015 Nov 17.

Genome Structure Research Center, KRIBB, Daejeon 305-806, Republic of Korea; Functional Genomics, Korea University of Science and Technology, Daejeon 305-350, Republic of Korea.

DNA damage induced apoptosis suppressor (DDIAS), or human Noxin (hNoxin), is strongly expressed in lung cancers. DDIAS knockdown induced apoptosis in non-small cell lung carcinoma A549 cells in response to DNA damage, indicating DDIAS as a potential therapeutic target in lung cancer. To understand the transcriptional regulation of DDIAS, we determined the transcription start site, promoter region, and transcription factor. We found that DDIAS transcription begins at nucleotide 212 upstream of the DDIAS translation start site. We cloned the DDIAS promoter region and identified NFAT2 as a major transcription factor (Im et al., 2016 [1]). We demonstrated that NFATc1 regulates DDIAS expression in both pancreatic cancer Panc-1 cells and lung cancer cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.dib.2015.11.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4675896PMC
December 2015

Antioxidant activities of distiller dried grains with solubles as protein films containing tea extracts and their application in the packaging of pork meat.

Food Chem 2016 Apr 8;196:174-9. Epub 2015 Sep 8.

Department of Food Science and Technology, Chungnam National University, Daejeon 305-764, Republic of Korea. Electronic address:

Distiller dried grains with solubles (DDGS) as protein (DP) films were prepared. Additionally, to prepare anti-oxidant films, green tea extract (GTE), oolong tea extract (OTE), and black tea extract (BTE) were incorporated into the DP films. Consequently, the incorporation of the tea extracts did not alter the physical properties of the films much, whereas the antioxidant activities, such as ABTS and DPPH radical scavenging activities were observed. To apply the DP films containing tea extracts to food packaging, pork meat was wrapped with the films and stored at 4 °C for 10 d. During storage, the pork meat wrapped with the DP films containing GTE, OTE, and BTE had less lipid oxidation than did the control. Among the tea extracts, the DP film containing GTE had the greatest antioxidant activity. These results indicate that the DP films containing green tea extracts can be utilized as an anti-oxidative packaging material for pork meat.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.foodchem.2015.09.020DOI Listing
April 2016

DNA damage-induced apoptosis suppressor (DDIAS), a novel target of NFATc1, is associated with cisplatin resistance in lung cancer.

Biochim Biophys Acta 2016 Jan 25;1863(1):40-9. Epub 2015 Oct 25.

Genome Structure Research Center, KRIBB, Daejeon 305-806, Republic of Korea; Functional Genomics, Korea University of Science and Technology, Daejeon 305-350, Republic of Korea. Electronic address:

In a previous study, we reported that DNA damage induced apoptosis suppressor (DDIAS; hNoxin), a human homolog of mouse Noxin, functions as an anti-apoptotic protein in response to DNA repair. Here we reveal that DDIAS is a target gene of nuclear factor of activated T cells 2 (NFATc1) and is associated with cisplatin resistance in lung cancer cells. In the DDIAS promoter analysis, we found that NFATc1 activated the transcription of DDIAS through binding to NFAT consensus sequences in the DDIAS promoter. In addition, tissue array immunostaining revealed a correlation between DDIAS and NFATc1 expression in human lung tumors. NFATc1 knockdown or treatment with the NFAT inhibitor cyclosporine A induced apoptosis and led to growth inhibition of lung cancer cells, indicating the functional relevance of both the proteins. In contrast, DDIAS overexpression overcame this NFATc1 knockdown-induced growth inhibition, supporting the cancer-specific role of DDIAS as a target gene of NFATc1. NFATc1 or DDIAS inhibition clearly enhanced apoptosis induced by cisplatin in NCI-H1703 and A549 cells. Conversely, DDIAS overexpression rescued NCI-H1703 cells from cisplatin-mediated cell death and caspase-3/7 activation. These results suggest that NFATc1-induced DDIAS expression contributes to cisplatin resistance, and targeting DDIAS or NFATc1 impairs the mechanism regulating cisplatin resistance in lung cancer cells. Taken together, DDIAS is a target of NFATc1 and is associated with cisplatin resistance in lung cancer cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbamcr.2015.10.011DOI Listing
January 2016

Synthesis and structure-activity relationship study of chemical probes as hypoxia induced factor-1α/malate dehydrogenase 2 inhibitors.

J Med Chem 2014 Nov 12;57(22):9522-38. Epub 2014 Nov 12.

BK21Plus R-FIND Team, College of Pharmacy, Dongguk University-Seoul , Koyang, 410-820, Korea.

A structure-activity relationship study of hypoxia inducible factor-1α inhibitor 3-aminobenzoic acid-based chemical probes, which were previously identified to bind to mitochondrial malate dehydrogenase 2, was performed to provide a better understanding of the pharmacological effects of LW6 and its relation to hypoxia inducible factor-1α (HIF-1α) and malate dehydrogenase 2 (MDH2). A variety of multifunctional probes including the benzophenone or the trifluoromethyl diazirine for photoaffinity labeling and click reaction were prepared and evaluated for their biological activity using a cell-based HRE-luciferase assay as well as a MDH2 assay in human colorectal cancer HCT116 cells. Among them, the diazirine probe 4a showed strong inhibitory activity against both HIF-1α and MDH2. Significantly, the inhibitory effect of the probes on HIF-1α activity was consistent with that of the MDH2 enzyme assay, which was further confirmed by the effect on in vitro binding activity to recombinant human MDH2, oxygen consumption, ATP production, and AMP activated protein kinase (AMPK) activation. Competitive binding modes of LW6 and probe 4a to MDH2 were also demonstrated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jm501241gDOI Listing
November 2014

p300 cooperates with c-Jun and PARP-1 at the p300 binding site to activate RhoB transcription in NSC126188-mediated apoptosis.

Biochim Biophys Acta 2014 May 15;1839(5):364-73. Epub 2014 Mar 15.

BioMedical Genomics Research Center, KRIBB, Daejeon 305-806, Korea; Functional Genomics, University of Science and Technology, Daejeon 305-350, Korea. Electronic address:

The anti-cancer agent NSC126188 induces apoptosis of stomach carcinoma NUGC-3 cells by inducing RhoB expression. Here, we present that the p300 binding site in the RhoB promoter is crucial for the binding of p300 and its partner transcription factors to activate RhoB transcription in NSC126188-mediated apoptosis. NSC126188 increased expression of p300 and c-Jun. Conversely, knockdown of p300 decreased RhoB expression in the presence of NSC126188. We found that poly(ADP-ribose) polymerase-1 (PARP-1) was associated with the p300 binding site and that PARP-1 knockdown inhibited NSC126188-mediated RhoB expression. In the cells treated with NSC126188, p300, PARP-1, and c-Jun interacted and bound the p300 binding site. Furthermore, chromatin immunoprecipitation (ChIP) analysis revealed strong p300 binding and weak c-Jun binding at the p300 binding site of RhoB promoter in cells treated with NSC126188. We also demonstrated that c-Jun played a crucial role in p300 binding. However, PARP-1 did not directly bind the p300 binding site, suggesting a bridging role between p300 and c-Jun. Electrophoretic mobility shift assays demonstrated a complex comprising p300/c-Jun/PARP-1 that bound wild type, but not a mutated, p300 binding site. In addition, overexpression of p300, PARP-1, or c-Jun dramatically enhanced RhoB promoter activity when it contained the wild type sequence but not mutated sequences, indicating the crucial role of the p300 binding site in NSC126188-induced transcription of RhoB. Taken together, these data suggest that p300 is recruited and cooperates with c-Jun and PARP-1 at the p300 binding site to activate RhoB transcription during NSC126188-mediated apoptosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbagrm.2014.03.004DOI Listing
May 2014

Human Noxin is an anti-apoptotic protein in response to DNA damage of A549 non-small cell lung carcinoma.

Int J Cancer 2014 Jun 29;134(11):2595-604. Epub 2013 Nov 29.

Medical Genomics Research Center, KRIBB, Daejeon, Korea; Functional Genomics, University of Science and Technology, Daejeon, Korea.

Human Noxin (hNoxin, C11Orf82), a homolog of mouse noxin, is highly expressed in colorectal and lung cancer tissues. hNoxin contains a DNA-binding C-domain in RPA1, which mediates DNA metabolic processes, such as DNA replication and DNA repair. Expression of hNoxin is associated with S phase in cancer cells and in normal cells. Expression of hNoxin was induced by ultraviolet (UV) irradiation. Knockdown of hNoxin caused growth inhibition of colorectal and lung cancer cells. The comet assay and western blot analysis revealed that hNoxin knockdown induced apoptosis through activation of p38 mitogen-activated protein kinase (MAPK)/p53 in non-small cell lung carcinoma A549 cells. Furthermore, simultaneous hNoxin knockdown and treatment with DNA-damaging agents, such as camptothecin (CPT) and UV irradiation, enhanced apoptosis, whereas Trichostatin A (TSA) did not. However, transient overexpression of hNoxin rescued cells from DNA damage-induced apoptosis but did not block apoptosis in the absence of DNA damage. These results suggest that hNoxin may be associated with inhibition of apoptosis in response to DNA damage. An adenovirus expressing a short hairpin RNA against hNoxin transcripts significantly suppressed the growth of A549 tumor xenografts, indicating that hNoxin knockdown has in vivo anti-tumor efficacy. Thus, hNoxin is a DNA damage-induced anti-apoptotic protein and potential therapeutic target in cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.28600DOI Listing
June 2014

A novel antitumor piperazine alkyl compound causes apoptosis by inducing RhoB expression via ROS‑mediated c‑Abl/p38 MAPK signaling.

Cancer Chemother Pharmacol 2013 Dec;72(6):1315-24

Purpose: We investigated the action mechanism of a novel anticancer compound, KR28 (1-allyl-4-dodecanoyl-1-ethyl-piperazin-1-ium; bromide), to induce apoptosis of human prostate carcinoma PC-3 cells.

Methods: To explore an apoptotic signaling of KR28, we used ROS assay, SRB assay, flow cytometry analysis, reporter assay, xenograft assay, Western blotting, and RT-PCR analysis.

Results: The growth inhibitory action of KR28 is cell line specific, impeding the growth of prostate carcinoma PC-3 and stomach carcinoma NUGC-3 cells. KR28 showed strong antitumor activity in PC-3 mouse xenograft model. KR28 increased ROS production, leading to nuclear c-Abl expression, which in turn activated p38 mitogen-activated protein kinase (MAPK) to enhance the expression of RhoB, an apoptosis inducer. The KR28-induced apoptosis was abrogated by the ROS scavenger N-acetylcysteine and by knockdown of c-Abl, p38 MAPK, or ATF2. Moreover, the p300 binding site and two CCAAT boxes in the RhoB promoter appear to be involved in ROS-mediated RhoB expression in the presence of KR28.

Conclusion: The antitumor agent KR28 induces apoptosis of PC-3 cells by ROS-mediated RhoB expression via c-Abl upregulation and activation of p38 MAPK/ATF-2.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00280-013-2310-yDOI Listing
December 2013

New synthetic aliphatic sulfonamido-quaternary ammonium salts as anticancer chemotherapeutic agents.

Eur J Med Chem 2013 Nov 21;69:670-7. Epub 2013 Sep 21.

Translational Research Center for Protein Function Control, Department of Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.

RhoB is expressed during tumor cell proliferation, survival, invasion, and metastasis. In malignant progression, the expression levels of RhoB are commonly attenuated. RhoB is known to be linked to the regulation of the PI3K/Akt survival pathways. Based on aliphatic amido-quaternary ammonium salts that induce apoptosis via up-regulation of RhoB, we synthesized novel aliphatic sulfonamido-quaternary ammonium salts. These new synthetic compounds were evaluated for their biological activities using an in vitro RhoB promoter assay in HeLa cells, and in a growth inhibition assay using human cancer cell lines including PC-3, NUGC-3, MDA-MB-231, ACHN, HCT-15, and NCI-H23. Compound 5b (ethyl-dimethyl-{3-[methyl-(tetradecane-1-sulfonyl)-amino]-propyl}-ammonium; iodide) was the most promising anticancer agent in the series, based upon the potency of growth inhibition and RhoB promotion. These new aliphatic sulfonamido-quaternary ammonium salts could be a valuable series for development of new anticancer chemotherapeutic agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2013.09.022DOI Listing
November 2013

NSC126188 induces apoptosis of prostate cancer PC-3 cells through inhibition of Akt membrane translocation, FoxO3a activation, and RhoB transcription.

Apoptosis 2014 Jan;19(1):179-90

Medical Genome Research Center, KRIBB, Taejon, 305-806, Korea.

We previously reported that NSC126188 caused apoptosis of cancer cells by inducing expression of RhoB. We here present that NSC126188 induces apoptosis of prostate cancer PC-3 cells by inhibiting Akt/FoxO3 signaling, which mediates RhoB upregulation. The apoptosis and Akt dephosphorylation caused by NSC126188 was not substantially relieved by overexpressing wild-type Akt but was relieved by overexpressing constitutively active Akt (CA-Akt) or myristoylated Akt (myr-Akt). Furthermore, overexpression of CA-Akt or myr-Akt downregulated RhoB expression, indicating that RhoB expression is regulated by Akt signaling. Interestingly, membrane translocation of GFP-Akt by insulin exposure was abolished in the cells pretreated with NSC126188 suggesting that NSC126188 directly interfered with translocation of Akt to the plasma membrane. In addition, NSC126188 activated FoxO3a by dephosphorylating S253 via Akt inhibition. Activated FoxO3a translocated to the nucleus and increased transcription of RhoB and other target genes. PC-3 cells transiently overexpressing FoxO3a exhibited increased RhoB expression and apoptosis in response to NSC126188. Conversely, FoxO3a knockdown reduced NSC126188-induced RhoB expression and cell death. These results suggest that RhoB may be a target gene of FoxO3a and is regulated by Akt signaling. Taken together, NSC126188 induces apoptosis of PC-3 cells by interfering with membrane recruitment of Akt, resulting in Akt dephosphorylation and FoxO3a activation, which leads to transcription of RhoB.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10495-013-0905-8DOI Listing
January 2014

Identification of malate dehydrogenase 2 as a target protein of the HIF-1 inhibitor LW6 using chemical probes.

Angew Chem Int Ed Engl 2013 Sep 9;52(39):10286-9. Epub 2013 Aug 9.

College of Pharmacy, Dongguk University-Seoul, 26 Pildong, Junggu, Seoul 100-715 (Korea).

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/anie.201304987DOI Listing
September 2013
-->