Abstract 3814: Metformin induces ER stress-dependent apoptosis through miR-708-5p/NNAT pathway in prostate cancer

Previous studies showed that metformin is associated with lower risk of tumorigenesis for several cancer types including prostate cancer. However, the molecular basis of anti-tumor effect induced by this biguanide agent is still unclear. In this study, we identified miR-708-5p as a novel downstream effector of metformin in prostate cancer. By increasing the expression of miR-708-5p, metformin suppresses the expression of endoplasmic reticulum (ER) membrane protein neuronatin (NNAT) and subsequently induces apoptosis of prostate cancer cells through ER stress pathway. Notably, down-regulated NNAT is associated with down-regulated intracellular calcium level and induces malformation of endoplasmic reticulum-ribosome structure which is revealed by electronic microscopy. Furthermore, western blot shows that the unfolded-protein response (UPR) proteins including CHOP, p-eIF2α, Calreticulin, GRP78 and ATP2A1, all of which are also considered as the ER stress markers, were up-regulated by metformin and miR-708-5p. Importantly, an increased apoptosis of prostate cancer cells is also observed when miR-708-5p mimic or NNAT siRNA was introduced. In summary, our findings clearly reveals that metformin stimulates miR-708-5p to target on NNAT mediated response to ER stress and apoptosis. This novel regulatory mechanism of metformin in prostate cancer cells not only advances our knowledge on the molecular mechanism of metformin in cancer progression, but also provide a promising therapeutic target for prostate cancer treatment. Citation Format: Jian Yang, Juncheng Wei, Yushi Wu, Zhilin Wang, Yuqi Guo, Xin Li. Metformin induces ER stress-dependent apoptosis through miR-708-5p/NNAT pathway in prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3814. doi:10.1158/1538-7445.AM2015-3814