GSK1059615 kills head and neck squamous cell carcinoma cells possibly via activating mitochondrial programmed necrosis pathway

// Jing Xie 1 , Quan Li 2 , Xi Ding 1 and Yunyun Gao 1 1 Department of Stomatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China 2 Center of Stomatology, The Second Affiliated Hospital of Soochow University, Suzhou, China Correspondence to: Jing Xie, email: xiejingwenzhou9@163.com Keywords: HNSCC, PI3K-AKT-mTOR, GSK1059615, programmed necrosis Received: November 23, 2016      Accepted: January 11, 2017      Published: February 07, 2017 ABSTRACT This study tested the anti-head and neck squamous cell carcinoma (HNSCC) cell activity by GSK1059615, a novel PI3K and mTOR dual inhibitor. GSK1059615 inhibited survival and proliferation of established (SCC-9, SQ20B and A253 lines) and primary human HNSCC cells. GSK1059615 blocked PI3K-AKT-mTOR activation in HNSCC cells. Intriguingly, GSK1059615 treatment in HNSCC cells failed to provoke apoptosis, but induced programmed necrosis. The latter was tested by mitochondria depolarization, ANT-1-cyclophilin-D mitochondrial association and lactate dehydrogenase (LDH) release. Reversely, mPTP blockers (sanglifehrin A, cyclosporin A and bongkrekic acid) or cyclophilin-D shRNA dramatically alleviated GSK1059615-induced SCC-9 cell death. Further studies demonstrated that GSK1059615 i.p. injection suppressed SCC-9 tumor growth in nude mice, which was compromised with co-administration with cyclosporin A. Thus, targeting PI3K-AKT-mTOR pathway by GSK1059615 possibly provokes programmed necrosis pathway to kill HNSCC cells.