Suppression of galectin‐3 expression enhances apoptosis and chemosensitivity in liver fluke‐associated cholangiocarcinoma

Cholangiocarcinoma (CCA) is a fatal disease with high resistance to anticancer drugs. This is probably in part due to enhanced resistance to apoptosis. We have previously shown that galectin‐3 (Gal‐3), a β‐galactoside‐binding lectin, is highly expressed in CCA tissues. In this study, we demonstrated further that Gal‐3 plays a direct role in anti‐apoptosis regardless of the apoptotic insults. The anti‐apoptotic activity and chemoresistance of CCA cells were related to Gal‐3 expression level. Suppression of Gal‐3 expression with siRNA stimulated apoptosis. siGal‐3‐K626 transiently depleted Gal‐3 expression to the baseline and dramatically induced apoptosis, while siGal‐3‐K402 suppressed Gal‐3 expression by 50% and provoked cell apoptosis, but only under apoptotic insults (hypoxic conditions or short UV radiation). These actions were reversed in Gal‐3 overexpressing CCA cells. The correlation between the degree of anti‐apoptotic activity and the level of endogenous Gal‐3 was demonstrated. Suppression of Gal‐3 expression in CCA cells with siGal‐3‐K402 significantly enhanced apoptosis induced by cisplatin or 5‐fluorouracil by approximately 10 times, whereas overexpression of Gal‐3 led to an increased resistance to drugs. In summary, the present study showed that the cellular level of Gal‐3 might contribute to the anti‐apoptotic activity and chemoresistance of CCA cells. Hence, Gal‐3 expression level in cancer cells or tissues may be a marker for predicting chemotherapeutic response, and Gal‐3 may be a specific gene‐targeting therapy option for treating CCA. (Cancer Sci 2009; 00: 000–000)