Dual PI-3 kinase/mTOR inhibition impairs autophagy flux and induces cell death independent of apoptosis and necroptosis
dc.contributor.author | Button, RW | |
dc.contributor.author | Vincent, JH | |
dc.contributor.author | Strang, CJ | |
dc.contributor.author | Luo, Shouqing | |
dc.date.accessioned | 2017-01-04T14:32:13Z | |
dc.date.available | 2017-01-04T14:32:13Z | |
dc.date.issued | 2016-01-22 | |
dc.identifier.issn | 1949-2553 | |
dc.identifier.issn | 1949-2553 | |
dc.identifier.uri | http://hdl.handle.net/10026.1/8192 | |
dc.description.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. | |
dc.format.extent | 5157-5175 | |
dc.format.medium | ||
dc.language | en | |
dc.language.iso | en | |
dc.publisher | Impact Journals, LLC | |
dc.subject | PI3KC3 | |
dc.subject | apoptosis | |
dc.subject | autophagy | |
dc.subject | mTOR | |
dc.subject | necroptosis | |
dc.subject | Apoptosis | |
dc.subject | Autophagy | |
dc.subject | Cell Death | |
dc.subject | Cell Line, Tumor | |
dc.subject | HeLa Cells | |
dc.subject | Humans | |
dc.subject | Necrosis | |
dc.subject | Phosphatidylinositol 3-Kinases | |
dc.subject | Phosphoinositide-3 Kinase Inhibitors | |
dc.subject | Signal Transduction | |
dc.subject | TOR Serine-Threonine Kinases | |
dc.subject | Transfection | |
dc.title | Dual PI-3 kinase/mTOR inhibition impairs autophagy flux and induces cell death independent of apoptosis and necroptosis | |
dc.type | journal-article | |
dc.type | Journal Article | |
dc.type | Research Support, Non-U.S. Gov't | |
plymouth.author-url | https://www.ncbi.nlm.nih.gov/pubmed/26814436 | |
plymouth.issue | 5 | |
plymouth.volume | 7 | |
plymouth.publication-status | Published | |
plymouth.journal | Oncotarget | |
dc.identifier.doi | 10.18632/oncotarget.6986 | |
plymouth.organisational-group | /Plymouth | |
plymouth.organisational-group | /Plymouth/Faculty of Health | |
plymouth.organisational-group | /Plymouth/Faculty of Health/Peninsula Medical School | |
plymouth.organisational-group | /Plymouth/REF 2021 Researchers by UoA | |
plymouth.organisational-group | /Plymouth/REF 2021 Researchers by UoA/UoA01 Clinical Medicine | |
plymouth.organisational-group | /Plymouth/Research Groups | |
plymouth.organisational-group | /Plymouth/Research Groups/Institute of Translational and Stratified Medicine (ITSMED) | |
plymouth.organisational-group | /Plymouth/Research Groups/Institute of Translational and Stratified Medicine (ITSMED)/CBR | |
plymouth.organisational-group | /Plymouth/Users by role | |
plymouth.organisational-group | /Plymouth/Users by role/Academics | |
plymouth.organisational-group | /Plymouth/Users by role/Researchers in ResearchFish submission | |
dc.publisher.place | United States | |
dcterms.dateAccepted | 2016-01-18 | |
dc.identifier.eissn | 1949-2553 | |
dc.rights.embargoperiod | No embargo | |
rioxxterms.versionofrecord | 10.18632/oncotarget.6986 | |
rioxxterms.licenseref.uri | http://www.rioxx.net/licenses/all-rights-reserved | |
rioxxterms.licenseref.startdate | 2016-01-22 | |
rioxxterms.type | Journal Article/Review | |
plymouth.funder | Tackling autophagy and apoptosis for the potential therapy of Huntington's Disease::MRC |