Oncotarget

Research Papers:

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

Jing Xie _, Quan Li, Xi Ding and Yunyun Gao

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Oncotarget. 2017; 8:50814-50823. https://doi.org/10.18632/oncotarget.15135

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Abstract

Jing Xie1, Quan Li2, Xi Ding1 and Yunyun Gao1

1Department of Stomatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China

2Center 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.


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