Anti-apoptotic phenotypes of cholestan-3 beta,5 alpha,6 beta-triol-resistant human cholangiocytes: Characteristics contributing to the genesis of cholangiocarcinoma

作者：Jusakul Apinya; Loilome Watcharin; Namwat Nisana; Techasen Anchalee; Kuver Rahul; Ioannou George N; Savard Christopher; Haigh W Geoffrey; Yongvanit Puangrat^*

来源：Journal of Steroid Biochemistry and Molecular Biology, 2013, 138: 368-375.

DOI：10.1016/j.jsbmb.2013.08.004

• Oxysterols
• Cholestan-3 beta,5 alpha,6 beta-triol
• Cholangiocarcinoma
• Apoptosis
• MMNK-1 cells

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.

• 出版日期2013-11