Suppressing ERK Pathway Impairs Glycochenodeoxycholate-Mediated Survival and Drug-Resistance in Hepatocellular Carcinoma Cells
Glycochenodeoxycholate (GCDA), a toxic component in bile salts, is involved in carcinogenesis of gastrointestinal tumors. The objective of this research was to study the function of ERK1/2 in the GCDA-mediated survival and drug-resistance in hepatocellular carcinoma cells (HCCs). Firstly, extracellu...
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| Format: | Article |
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Frontiers Media S.A.
2021-07-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.663944/full |
| _version_ | 1818863426264367104 |
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| author | Bingxin Li Maojun Zhou Jue Wang Hongjuan Xu Manyi Yang |
| author_facet | Bingxin Li Maojun Zhou Jue Wang Hongjuan Xu Manyi Yang |
| author_sort | Bingxin Li |
| collection | DOAJ |
| description | Glycochenodeoxycholate (GCDA), a toxic component in bile salts, is involved in carcinogenesis of gastrointestinal tumors. The objective of this research was to study the function of ERK1/2 in the GCDA-mediated survival and drug-resistance in hepatocellular carcinoma cells (HCCs). Firstly, extracellular signal-regulated kinase 1/2 (ERK1/2) was detected extensively expressed in liver cancer cells, and silencing ERK1/2 by RNA interference could suppress GCDA-stimulated survival and promote apoptosis. Furthermore, phosphorylation of endogenous ERK1/2 could be potently stimulated by GCDA in combination with enhanced chemoresistance in QGY-7703 hepatocellular carcinoma cells. The GCDA-mediated proliferation and chemoresistance could be impaired by PD98059, which acted as an inhibitor to block the phosphorylation of ERK1/2. Mechanistically, PD98059 was able to potently suppress GCDA-stimulated nuclear aggregation of ERK1/2 and p-ERK1/2, upregulate pro-survival protein Mcl-1 and downregulate pro-apoptotic protein Bim. The results of this study indicated that disruption of ERK1/2 by blocking phosphorylation or nuclear translocation may put forward new methods for solving the problem of GCDA-related proliferation and drug-resistance in liver cancer treatment. |
| first_indexed | 2024-12-19T10:15:34Z |
| format | Article |
| id | doaj.art-ed00fe526a454291991a56a2e1bf1725 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-19T10:15:34Z |
| publishDate | 2021-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-ed00fe526a454291991a56a2e1bf17252022-12-21T20:26:15ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-07-011110.3389/fonc.2021.663944663944Suppressing ERK Pathway Impairs Glycochenodeoxycholate-Mediated Survival and Drug-Resistance in Hepatocellular Carcinoma CellsBingxin Li0Maojun Zhou1Jue Wang2Hongjuan Xu3Manyi Yang4Department of Hepatobiliary and Pancreatic Surgery, National Health Commission (NHC) Key Laboratory of Nanobiological Technology, Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Oncology, NHC Key Laboratory of Cancer Proteomics, National Center for Geriatrics Clinical Research, State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Hepatobiliary and Pancreatic Surgery, National Health Commission (NHC) Key Laboratory of Nanobiological Technology, Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Hepatobiliary and Pancreatic Surgery, National Health Commission (NHC) Key Laboratory of Nanobiological Technology, Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Hepatobiliary and Pancreatic Surgery, National Health Commission (NHC) Key Laboratory of Nanobiological Technology, Xiangya Hospital, Central South University, Changsha, ChinaGlycochenodeoxycholate (GCDA), a toxic component in bile salts, is involved in carcinogenesis of gastrointestinal tumors. The objective of this research was to study the function of ERK1/2 in the GCDA-mediated survival and drug-resistance in hepatocellular carcinoma cells (HCCs). Firstly, extracellular signal-regulated kinase 1/2 (ERK1/2) was detected extensively expressed in liver cancer cells, and silencing ERK1/2 by RNA interference could suppress GCDA-stimulated survival and promote apoptosis. Furthermore, phosphorylation of endogenous ERK1/2 could be potently stimulated by GCDA in combination with enhanced chemoresistance in QGY-7703 hepatocellular carcinoma cells. The GCDA-mediated proliferation and chemoresistance could be impaired by PD98059, which acted as an inhibitor to block the phosphorylation of ERK1/2. Mechanistically, PD98059 was able to potently suppress GCDA-stimulated nuclear aggregation of ERK1/2 and p-ERK1/2, upregulate pro-survival protein Mcl-1 and downregulate pro-apoptotic protein Bim. The results of this study indicated that disruption of ERK1/2 by blocking phosphorylation or nuclear translocation may put forward new methods for solving the problem of GCDA-related proliferation and drug-resistance in liver cancer treatment.https://www.frontiersin.org/articles/10.3389/fonc.2021.663944/fullhepatocellular carcinoma cellsglycochenodeoxycholateextracellular signal-regulated kinase 1/2anti-apoptosis proteinspro-apoptotic proteins |
| spellingShingle | Bingxin Li Maojun Zhou Jue Wang Hongjuan Xu Manyi Yang Suppressing ERK Pathway Impairs Glycochenodeoxycholate-Mediated Survival and Drug-Resistance in Hepatocellular Carcinoma Cells Frontiers in Oncology hepatocellular carcinoma cells glycochenodeoxycholate extracellular signal-regulated kinase 1/2 anti-apoptosis proteins pro-apoptotic proteins |
| title | Suppressing ERK Pathway Impairs Glycochenodeoxycholate-Mediated Survival and Drug-Resistance in Hepatocellular Carcinoma Cells |
| title_full | Suppressing ERK Pathway Impairs Glycochenodeoxycholate-Mediated Survival and Drug-Resistance in Hepatocellular Carcinoma Cells |
| title_fullStr | Suppressing ERK Pathway Impairs Glycochenodeoxycholate-Mediated Survival and Drug-Resistance in Hepatocellular Carcinoma Cells |
| title_full_unstemmed | Suppressing ERK Pathway Impairs Glycochenodeoxycholate-Mediated Survival and Drug-Resistance in Hepatocellular Carcinoma Cells |
| title_short | Suppressing ERK Pathway Impairs Glycochenodeoxycholate-Mediated Survival and Drug-Resistance in Hepatocellular Carcinoma Cells |
| title_sort | suppressing erk pathway impairs glycochenodeoxycholate mediated survival and drug resistance in hepatocellular carcinoma cells |
| topic | hepatocellular carcinoma cells glycochenodeoxycholate extracellular signal-regulated kinase 1/2 anti-apoptosis proteins pro-apoptotic proteins |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2021.663944/full |
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