title: Dual PI-3 kinase/mTOR inhibition impairs autophagy flux and induces cell death independent of apoptosis and necroptosis.
abstract: The PI-3 kinase (PI-3K)/mTOR pathway is critical for cell growth and proliferation. Strategies of antagonising this signaling have proven to be detrimental to cell survival. This observation, coupled with the fact many tumours show enhanced growth signaling, has caused dual inhibitors of PI-3K and mTOR to be implicated in cancer treatment, and have thus been studied across various tumour models. Since PI-3K (class-I)/mTOR pathway negatively regulates autophagy, dual inhibitors of PI-3K/mTOR are currently believed to be autophagy activators. However, our present data show that the dual PI-3K/mTOR inhibition (DKI) potently suppresses autophagic flux. We further confirm that inhibition of Vps34/PI3KC3, the class-III PI-3K, causes the blockade to autophagosome-lysosome fusion. Our data suggest that DKI induces cell death independently of apoptosis and necroptosis, whereas autophagy perturbation by DKI may contribute to cell death. Given that autophagy is critical in cellular homeostasis, our study not only clarifies the role of a dual PI-3K/mTOR inhibitor in autophagy, but also suggests that its autophagy inhibition needs to be considered if such an agent is used in cancer chemotherapy.
authors.affiliation: Peninsula Schools of Medicine and Dentistry, Institute of Translational and Stratified Medicine, University of Plymouth, Research Way, Plymouth, UK.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Button
authors.affiliation: Peninsula Schools of Medicine and Dentistry, Institute of Translational and Stratified Medicine, University of Plymouth, Research Way, Plymouth, UK.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Vincent
authors.affiliation: Peninsula Schools of Medicine and Dentistry, Institute of Translational and Stratified Medicine, University of Plymouth, Research Way, Plymouth, UK.
authors.forename: Conor J
authors.initials: CJ
authors.lastname: Strang
authors.affiliation: Peninsula Schools of Medicine and Dentistry, Institute of Translational and Stratified Medicine, University of Plymouth, Research Way, Plymouth, UK.
authors.forename: Shouqing
authors.initials: S
authors.lastname: Luo
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D001343:Autophagy; D016923:Cell Death; D045744:Cell Line, Tumor; D006367:HeLa Cells; D006801:Humans; D009336:Necrosis / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014162:Transfection
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human
keywords: PI3KC3; apoptosis; autophagy; mTOR; necroptosis
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