Atorvastatin Augments Gemcitabine-Mediated Anti-Cancer Effects by Inhibiting Yes-Associated Protein in Human Cholangiocarcinoma Cells.

Abstract

Cholangiocarcinoma (CCA) is associated with high mortality rates because of its resistance to conventional gemcitabine-based chemotherapy. Hydroxy-methyl-glutaryl-coenzyme A reductase inhibitors (statins) reportedly exert anti-cancer effects in CCA and lower the risk of CCA; however, the underlying mechanism of these effects remains unclear. The proliferative and oncogenic activities of the transcriptional co-activator Yes-associated protein (YAP) are driven by its association with the TEA domain (TEAD) of transcription factors; thereby, upregulating genes that promote cell growth, inhibit apoptosis, and confer chemoresistance. This study investigated the effects of atorvastatin in combination with gemcitabine on the progression of human CCA associated with YAP oncogenic regulation. Both atorvastatin and gemcitabine concentration-dependently suppressed the proliferation of HuCCT-1 and KKU-M213 human CCA cells. Moreover, both agents induced cellular apoptosis by upregulating the pro-apoptotic marker BAX and downregulating the anti-apoptotic markers MCL1 and BCL2. Atorvastatin also significantly decreased the mRNA expression of the TEAD target genes CTGF, CYR61, ANKRD1, and MFAP5 in both CCA cell lines. A xenograft tumor growth assay indicated that atorvastatin and gemcitabine potently repressed human CCA cell-derived subcutaneous tumor growth by inhibiting YAP nuclear translocation and TEAD transcriptional activation. Notably, the anti-cancer effects of the individual agents were significantly enhanced in combination. These results indicate that gemcitabine plus atorvastatin could serve as a potential novel treatment option for CCA.