scholarly journals Lucanthone, Autophagy Inhibitor, Enhances the Apoptotic Effects of TRAIL through miR-216a-5p-Mediated DR5 Upregulation and DUB3-Mediated Mcl-1 Downregulation

2021 ◽  
Vol 23 (1) ◽  
pp. 17
Author(s):  
Ji Yun Yoon ◽  
Seon Min Woo ◽  
Seung Un Seo ◽  
So Rae Song ◽  
Seul Gi Lee ◽  
...  
Keyword(s):  
Renal Carcinoma ◽  
Combined Treatment ◽  
Ectopic Expression ◽  
A549 Cells ◽  
Expression Level ◽  
Human Skin Fibroblast ◽  
Normal Human Skin ◽  
Induced Apoptosis ◽  
Apoptotic Effects ◽  
Human Renal Carcinoma

A lucanthone, one of the family of thioxanthenones, has been reported for its inhibitory effects of apurinic endonuclease-1 and autophagy. In this study, we investigated whether lucanthone could enhance tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in various cancer cells. Combined treatment with lucanthone and TRAIL significantly induced apoptosis in human renal carcinoma (Caki and ACHN), prostate carcinoma (PC3), and lung carcinoma (A549) cells. However, combined treatment did not induce apoptosis in normal mouse kidney cells (TCMK-1) and normal human skin fibroblast (HSF). Lucanthone downregulated protein expression of deubiquitinase DUB3, and a decreased expression level of DUB3 markedly led to enhance TRAIL-induced apoptosis. Ectopic expression of DUB3 inhibited combined treatment with lucanthone and TRAIL-induced apoptosis. Moreover, lucanthone increased expression level of DR5 mRNA via downregulation of miR-216a-5p. Transfection of miR-216a-5p mimics suppressed the lucanthone-induced DR5 upregulation. Taken together, these results provide the first evidence that lucanthone enhances TRAIL-induced apoptosis through DR5 upregulation by downregulation of miR-216a-5p and DUB3-dependent Mcl-1 downregulation in human renal carcinoma cells.

scholarly journals WP1130 Enhances TRAIL-Induced Apoptosis through USP9X-Dependent miR-708-Mediated Downregulation of c-FLIP

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 344 ◽  
Author(s):  
Seok Kim ◽  
Seon Woo ◽  
Kyoung-jin Min ◽  
Seung Seo ◽  
Tae-Jin Lee ◽  
...  
Keyword(s):  
Renal Carcinoma ◽  
Mesangial Cells ◽  
Combined Treatment ◽  
Ectopic Expression ◽  
Carcinoma Cells ◽  
Human Mesangial Cells ◽  
Dub Inhibitor ◽  
Induced Apoptosis ◽  
Sensitizing Effect ◽  
Human Renal Carcinoma

WP1130, a partially selective deubiquitinases (DUB) inhibitor, inhibits the deubiquitinating activities of USP5, USP9X, USP14, USP37, and UCHL1. In this study, we investigate whether WP1130 exerts sensitizing effect on TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human renal carcinoma cells. Combinations of WP1130 and TRAIL significantly induced apoptosis in renal carcinoma, lung carcinoma and hepatocellular carcinoma cells, but not in normal cells (human mesangial cells (MC) and normal mouse kidney cells (TCMK-1)). The downregulation of c-FLIP protein expression was involved in combined treatment-induced apoptosis. WP1130-induced c-FLIP downregulation was regulated by microRNA (miR)-708 upregulation via inhibition of USP9X. Interestingly, knockdown of USP9X markedly induced c-FLIP downregulation, upregulation of miR-708 expression and sensitivity to TRAIL. Furthermore, ectopic expression of USP9X prevented c-FLIP downregulation and apoptosis upon combined treatment. In sum, WP1130 sensitized TRAIL-induced apoptosis through miR-708-mediated downregulation of c-FLIP by inhibition of USP9X.

scholarly journals Cepharanthine Enhances TRAIL-Mediated Apoptosis Through STAMBPL1-Mediated Downregulation of Survivin Expression in Renal Carcinoma Cells

2018 ◽  
Vol 19 (10) ◽  
pp. 3280 ◽  
Author(s):  
Sk Shahriyar ◽  
Seon Woo ◽  
Seung Seo ◽  
Kyoung-jin Min ◽  
Taeg Kwon
Keyword(s):  
Renal Carcinoma ◽  
Apoptotic Cell ◽  
Combined Treatment ◽  
Ectopic Expression ◽  
Survivin Expression ◽  
Carcinoma Cells ◽  
Inhibitory Protein ◽  
Anticancer Properties ◽  
Induced Apoptosis ◽  
Renal Carcinoma Cells

Cepharanthine (CEP) is a natural plant alkaloid, and has anti-inflammatory, antineoplastic, antioxidative and anticancer properties. In this study, we investigated whether CEP could sensitize renal carcinoma Caki cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. CEP alone and TRAIL alone had no effect on apoptosis. However, combined CEP and TRAIL treatment markedly enhanced apoptotic cell death in cancer cells, but not in normal cells. CEP induced downregulation of survivin and cellular-FLICE inhibitory protein (c-FLIP) expression at post-translational levels. Ectopic expression of survivin blocked apoptosis by combined treatment with CEP plus TRAIL, but not in c-FLIP overexpression. Interestingly, CEP induced survivin downregulation through downregulation of deubiquitin protein of STAM-binding protein-like 1 (STAMBPL1). Overexpression of STAMBPL1 markedly recovered CEP-mediated survivin downregulation. Taken together, our study suggests that CEP sensitizes TRAIL-mediated apoptosis through downregulation of survivin expression at the post-translational levels in renal carcinoma cells.

scholarly journals Maritoclax Enhances TRAIL-Induced Apoptosis via CHOP-Mediated Upregulation of DR5 and miR-708-Mediated Downregulation of cFLIP

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 3030 ◽  
Author(s):  
Mi-Yeon Jeon ◽  
Kyoung-jin Min ◽  
Seon Woo ◽  
Seung Seo ◽  
Yung Choi ◽  
...  
Keyword(s):  
Renal Carcinoma ◽  
Combined Treatment ◽  
Ectopic Expression ◽  
Death Receptor ◽  
Death Receptor 5 ◽  
Active Constituent ◽  
Inhibitory Protein ◽  
Homologous Protein ◽  
Induced Apoptosis ◽  
Sensitizing Effect

Maritoclax, an active constituent isolated from marine bacteria, has been known to induce Mcl-1 downregulation through proteasomal degradation. In this study, we investigated the sensitizing effect of maritoclax on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human renal carcinoma cells. We found that combined treatment with maritoclax and TRAIL markedly induced apoptosis in renal carcinoma (Caki, ACHN and A498), lung cancer (A549) and hepatocellular carcinoma (SK-Hep1) cells. The upregulation of death receptor 5 (DR5) and downregulation of cellular FLICE-inhibitory protein (cFLIP) were involved in maritoclax plus TRAIL-induced apoptosis. Maritoclax-induced DR5 upregulation was regulated by induction of C/EBP homologous protein (CHOP) expression. Interestingly, maritoclax induced cFLIP downregulation through the increased expression of miR-708. Ectopic expression of cFLIP prevented combined maritoclax and TRAIL-induced apoptosis. Taken together, maritoclax sensitized TRAIL-induced apoptosis through CHOP-mediated DR5 upregulation and miR-708-mediated cFLIP downregulation.

scholarly journals Cancer cells activate p53 in response to 10-formyltetrahydrofolate dehydrogenase expression

2005 ◽  
Vol 391 (3) ◽  
pp. 503-511 ◽  
Author(s):  
Natalia V. Oleinik ◽  
Natalia I. Krupenko ◽  
David G. Priest ◽  
Sergey A. Krupenko
Keyword(s):  
Cancer Cells ◽  
Ectopic Expression ◽  
A549 Cells ◽  
Dominant Negative ◽  
G1 Arrest ◽  
Transactivation Domain ◽  
Downstream Target ◽  
Formyltetrahydrofolate Dehydrogenase ◽  
Induced Apoptosis ◽  
Hct116 Cells

A folate enzyme, FDH (10-formyltetrahydrofolate dehydrogenase; EC 1.5.1.6), is not a typical tumour suppressor, but it has two basic characteristics of one, i.e. it is down-regulated in tumours and its expression is selectively cytotoxic to cancer cells. We have recently shown that ectopic expression of FDH in A549 lung cancer cells induces G1 arrest and apoptosis that was accompanied by elevation of p53 and its downstream target, p21. It was not known, however, whether FDH-induced apoptosis is p53-dependent or not. In the present study, we report that FDH-induced suppressor effects are strictly p53-dependent in A549 cells. Both knockdown of p53 using an RNAi (RNA interference) approach and disabling of p53 function by dominant-negative inhibition with R175H mutant p53 prevented FDH-induced cytotoxicity in these cells. Ablation of the FDH-suppressor effect is associated with an inability to activate apoptosis in the absence of functional p53. We have also shown that FDH elevation results in p53 phosphorylation at Ser-6 and Ser-20 in the p53 transactivation domain, and Ser-392 in the C-terminal domain, but only Ser-6 is strictly required to mediate FDH effects. Also, translocation of p53 to the nuclei and expression of the pro-apoptotic protein PUMA (Bcl2 binding component 3) was observed after induction of FDH expression. Elevation of FDH in p53 functional HCT116 cells induced strong growth inhibition, while growth of p53-deficient HCT116 cells was unaffected. This implies that activation of p53-dependent pathways is a general downstream mechanism in response to induction of FDH expression in p53 functional cancer cells.

Endoplasmic reticulum stress mediates withaferin A-induced apoptosis in human renal carcinoma cells

2011 ◽  
Vol 25 (3) ◽  
pp. 692-698 ◽  
Author(s):  
Min Jung Choi ◽  
Eun Jung Park ◽  
Kyoung Jin Min ◽  
Jong-Wook Park ◽  
Taeg Kyu Kwon
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Renal Carcinoma ◽  
Carcinoma Cells ◽  
Withaferin A ◽  
Induced Apoptosis ◽  
Human Renal Carcinoma ◽  
Renal Carcinoma Cells

scholarly journals Inhibition of Drp1 Sensitizes Cancer Cells to Cisplatin-Induced Apoptosis through Transcriptional Inhibition of c-FLIP Expression

Molecules ◽  
2020 ◽  
Vol 25 (24) ◽  
pp. 5793
Author(s):  
Seon Min Woo ◽  
Kyoung-jin Min ◽  
Taeg Kyu Kwon
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Apoptotic Cell ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Combined Treatment ◽  
Ectopic Expression ◽  
Specific Inhibitor ◽  
Apoptotic Cell Death ◽  
Induced Apoptosis

Mitochondrial fragmentation occurs during the apoptosis. Dynamin-related protein 1 (Drp1) acts as an important component in mitochondrial fission machinery and can regulate various biological processes including apoptosis, cell cycle, and proliferation. The present study demonstrates that dysfunction of mitochondrial dynamics plays a pivotal role in cisplatin-induced apoptosis. Inhibiting the mitochondrial fission with the specific inhibitor (Mdivi-1) did not affect apoptotic cell death in low concentrations (<10 μM). Interestingly, mdivi-1 enhanced cisplatin-induced apoptosis in cancer cells, but not in normal cells. Particularly in the presence of mdivi-1, several human cancer cell lines, including renal carcinoma cell line Caki-1, became vulnerable to cisplatin by demonstrating the traits of caspase 3-dependent apoptosis. Combined treatment induced downregulation of c-FLIP expression transcriptionally, and ectopic expression of c-FLIP attenuated combined treatment-induced apoptotic cell death with mdivi-1 plus cisplatin. Collectively, our data provide evidence that mdivi-1 might be a cisplatin sensitizer.

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