Autophagy inhibition sensitizes LY3023414-induced anti-glioma cell activity in vitro and in vivo

// Lan Zheng 1, * , Huanyin Li 1, * , Yanqing Mo 1, * , Gong Qi 1 , Bin Liu 1 and Jing Zhao 1 1 Neurology Department, Minhang Hospital, Fudan University, Shanghai, China * Co-first authors Correspondence to: Jing Zhao, email: zhaojinmhyy7@163.com, zjmzx16f@126.com Lan Zheng, email: zhenglanwz2@163.com Keywords: glioma; PI3K-AKT-mTOR; LY3023414; autophagy; apoptosis Received: June 21, 2017      Accepted: July 13, 2017      Published: October 27, 2017 ABSTRACT PI3K-AKT-mTOR signaling is a valuable treatment target for human glioma. LY3023414 is a novel, highly-potent and pan PI3K-AKT-mTOR inhibitor. Here, we show that LY3023414 efficiently inhibited survival and proliferation of primary and established human glioma cells. Meanwhile, apoptosis activation was observed in LY3023414-treated glioma cells. LY3023414 blocked AKT-mTOR activation in human glioma cells. Further studies show that LY3023414 induced feedback activation of autophagy in U251MG cells. On the other hand, autophagy inhibition via adding pharmacological inhibitors or silencing Beclin-1/ATG-5 significantly potentiated LY3023414-induced glioma cell apoptosis. In vivo studies demonstrated that U251MG xenograft tumor growth in mice was suppressed by oral administration of LY3023414. Remarkably, LY3023414’s anti-tumor activity was further augmented against the Beclin-1-silenced U251MG tumors. Together, our results suggest that targeting PI3K-AKT-mTOR cascade by LY3023414 inhibits human glioma cell growth in vitro and in vivo . Autophagy inhibition could further sensitize LY3023414 against human glioma cells.