Long-term ethanol exposure causes human liver cancer cells to become resistant to mitomycin C treatment through the inactivation of bad-mediated apoptosis.
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| Abstract |
The aim of this study was to test whether long-term ethanol consumption confers therapeutic resistance to human liver cancer patients infected with hepatitis B virus (HBV). Chronic ethanol-treated cells were established by consecutively culturing a human hepatocellular carcinoma cell line, Hep 3B, which contains integrated HBV sequences, for 20-40 passages with or without 10 mM ethanol (designated as E20-E40 and C20-C40, respectively). Flow cytometry analysis demonstrated that a growth promoting effect of long-term ethanol treatment was induced in the E40 cells through preferential acceleration of S-phase in these cells. Lower protein expression levels of p16, p21/Cip1, and p27/Kip1 were detected in the ethanol-treated E40 cells. We further demonstrated that long-term ethanol-treated E40 cells develop drug resistance in response to mitomycin C (MMC) treatment (>8 microM). Immunoblot analysis revealed that caspase-8-mediated mitochondrial apoptotic signals (such as Bad) were inactivated in the MMC-resistant E40 cells. Immunoprecipitation experiments demonstrated that the sequestration of phosphorylated Bad (Ser-112) through its binding with 14-3-3 was detected more profoundly in the MMC-resistant E40 cells. Next, we examined the therapeutic efficacy of MMC (10 mg MMC/kg body weight, three times per week) in severe combined immunodeficient (SCID) mice bearing E40- and C40-xenografted tumors. Significant reductions (>3-fold) in tumor growth were detected in MMC-treated C40-xenografted mice. In vivo and in vitro studies demonstrated that AKT- and extracellular signal-regulated kinase (ERK)-mediated survival factors inhibited the Bad-induced mitochondrial apoptotic signals that were involved in E40 tumor cells and that conferred resistance to MMC.
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| Authors | Ching-Shui Huang, Yi-Ru Lee, Ching-Shyang Chen, Shih-Hsin Tu, Ying-Jan Wang, Chia-Hwa Lee, Li-Ching Chen, Hui-Wen Chang, Chien-Hsi Chang, Su Chih-Ming, Chih-Hsiung Wu, Yuan-Soon Ho |
| Journal | Molecular carcinogenesis (Mol Carcinog) Vol. 49 Issue 8 Pg. 728-38 (Aug 2010) ISSN: 1098-2744 [Electronic] United States |
| PMID | 20623640 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Copyright | Copyright (c) 2010 Wiley-Liss, Inc. |
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