Abstract 4734: Inhibitory effects of metformin on epithelial-mesenchymal transition of CD44+/CD117+ ovarian cancer stem cells

Abstract

Abstract Background: Although metformin, a first-line drug for treating diabetes, may play an important role in inhibition of epithelial ovarian cancer cell growth and cancer stem cells (CSCs), metformin at low dose showed less effect on proliferation of ovarian cancer cells. In this study, we evaluated the effect of metformin at low dose on ovarian CSCs in order to understand the molecular mechanisms underlying ovarian tumorigenesis. Methods: The inhibitory effects of metformin at los dose on proliferation and population of ovarian cancer cells including SKOV3 and A2780 were assessed by cell proliferation assay and flow cytometry. Quantitative real-time PCR assays on expression of Bcl-2, Survivin and Bax were performed to determine the effect of the metformin at low dose on epithelial-mesenchymal transition (EMT) of cancer cells and CSCs. Tumor sphere formation assay was also performed to evaluate the effect of metformin on spheres forming ability of CSCs. The therapeutic efficacy and the anti-CSC effects of metformin at low dose were investigated by using both SKOV3 cells and primary tumor xenografts. In addition, the CSC frequency and EMT in tumor xenograft models were also assessed by flow cytometry and quantitative real-time PCR. Results: Metformin at low dose did not affect proliferation of ovarian cancer cells, however, it inhibited the population of the CD44+/CD117+ selectively, neither CD133+ nor ALDH+ cells. It suppressed expression of snail2, twist and vimentin significantly in cancer cells and CD44+/CD117+ CSCs in vitro. Low dose of metformin reduced survivin expression in CSCs leading to arrest of cell cycle. Metformin at low concentration inhibited the secondary and the tertiary tumor sphere formation, decreased the growth of either SKOV3 or primary ovarian tumor xenograft, enhanced the anticancer effect of the cisplatin, and lowered the proportion of the CD44+/CD117+ CSCs in the xenograft tissue. Metformin was also associated with a reduction of snail2, twist, and vimentin in CD44+/CD117+ ovarian CSCs in vivo. Conclusions: Our results implicate that metformin at low dose inhibits selectively CD44+/CD117+ ovarian CSCs through inhibition of EMT and potentiates the effect of the cisplatin. Citation Format: Gary G. Xiao, Rongrong Zhang, Ping Zhang, Hong Wang, Dongming Hou, Wentao Li, Chenwei Li. Inhibitory effects of metformin on epithelial-mesenchymal transition of CD44+/CD117+ ovarian cancer stem cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4734.