Journal
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
Volume 138, Issue -, Pages 368-375Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jsbmb.2013.08.004
Keywords
Oxysterols; Cholestan-3 beta,5 alpha,6 beta-triol; Cholangiocarcinoma; Apoptosis; MMNK-1 cells
Funding
- Thailand Research Fund through the Royal Golden Jubilee Ph.D. Program [PHD/0177/2549]
- Thailand Research Fund through Window II [BRG 5280020]
- Higher Education Research Promotion and National Research University Project of Thailand, Office of the Higher Education Commission, through the Health Cluster (SHeP-GMS) Khon Kaen University
- NIH [CA114403]
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The oxysterols cholestan-3 beta,5 alpha,6 beta-triol (Triol) and 3-keto-cholest-4-ene (3K4) are increased in Opisthorchis viverrini-associated hamster cholangiocarcinoma and induce DNA damage and apoptosis via a mitochondria-dependent mechanism in MMNK-1 human cholangiocytes. Based on these observations, we hypothesized that chronic exposure of cholangiocytes to these pathogenic oxysterols may allow a growth advantage to a subset of these cells through selection for resistance to apoptosis, thereby contributing to cholangiocarcinogenesis. To test this hypothesis, we cultured MMNK-1 cells long-term in the presence of Triol. Alteration in survival and apoptotic factors of Triol-exposed cells were examined. Cells cultured long-term in the presence of Triol were resistant to H2O2-induced apoptosis, and demonstrated an increase in the phosphorylation of p38-alpha, CREB, ERK1/2 and c-Jun. Elevations in the ratio of Bcl-2/Bax and in the protein levels of anti-apoptotic factors including cIAP2, clusterin, and survivin were detected. These results show that long-term exposure of MNNK-1 cells to low doses of Triol selects for kinase-signaling molecules which regulate resistance to apoptosis and thereby enhance cell survival. Clonal expansion of such apoptosis-resistant cells may contribute to the genesis of cholangiocarcinoma. (C) 2013 Elsevier Ltd. All rights reserved.
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