ArticleCancer research2013
mTOR complex 2 is involved in regulation of Cbl-dependent c-FLIP degradation and sensitivity of TRAIL-induced apoptosis.
Article in Cancer research, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 37 citations in OpenAlex.
- Ethacrynic Oxadiazole 6u Induces Apoptosis by Targeting mTOR/c-Flip Axis and Noxa in Lymphoma Cells.Biological procedures online · 2026Article
- Integrating AI/ML and multi-omics approaches to investigate the role of TNFRSF10A/TRAILR1 and its potential targets in pancreatic cancer.Computers in biology and medicine · 2025Article
- Tubeimoside-1 Enhances TRAIL-Induced Apoptotic Cell Death through STAMBPL1-Mediated c-FLIP Downregulation.International journal of molecular sciences · 2023Article
- The Third-Generation EGFR Inhibitor, Osimertinib, Promotes c-FLIP Degradation, Enhancing Apoptosis Including TRAIL-Induced Apoptosis in NSCLC Cells with Activating EGFR Mutations.Translational oncology · 2019Article
- WP1130 Enhances TRAIL-Induced Apoptosis through USP9X-Dependent miR-708-Mediated Downregulation of c-FLIP.Cancers · 2019Article
- E3 ubiquitin ligases and deubiquitinases as modulators of TRAIL-mediated extrinsic apoptotic signaling pathway.BMB reports · 2019Review
- c-FLIP is a target of the E3 ligase deltex1 in gastric cancer.Cell death & disease · 2018Article
- Droxinostat sensitizes human colon cancer cells to apoptotic cell death via induction of oxidative stress.Cellular & molecular biology letters · 2018Article
- DR5-Cbl-b/c-Cbl-TRAF2 complex inhibits TRAIL-induced apoptosis by promoting TRAF2-mediated polyubiquitination of caspase-8 in gastric cancer cells.Molecular oncology · 2017Article
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- The proteasome deubiquitinase inhibitor b-AP15 enhances DR5 activation-induced apoptosis through stabilizing DR5.Scientific reports · 2017Article
- Metformin sensitizes triple-negative breast cancer to proapoptotic TRAIL receptor agonists by suppressing XIAP expression.Breast cancer research and treatment · 2017Article
- Thioridazine enhances sensitivity to carboplatin in human head and neck cancer cells through downregulation of c-FLIP and Mcl-1 expression.Cell death & disease · 2017Article
- Intrinsic cellular signaling mechanisms determine the sensitivity of cancer cells to virus-induced apoptosis.Scientific reports · 2016Article
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- Galangin sensitizes TRAIL-induced apoptosis through down-regulation of anti-apoptotic proteins in renal carcinoma Caki cells.Scientific reports · 2016Article
- FLIP the Switch: Regulation of Apoptosis and Necroptosis by cFLIP.International journal of molecular sciences · 2015Review
- mTOR Complex 2 Stabilizes Mcl-1 Protein by Suppressing Its Glycogen Synthase Kinase 3-Dependent and SCF-FBXW7-Mediated Degradation.Molecular and cellular biology · 2015Article
- Maintaining glycogen synthase kinase-3 activity is critical for mTOR kinase inhibitors to inhibit cancer cell growth.Cancer research · 2014Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
The mTOR positively regulates cell proliferation and survival through forming 2 complexes with raptor (mTOR complex 1; mTORC1) or rictor (mTOR complex 2; mTORC2). Compared with the mTORC1, relatively little is known about the biologic functions of mTORC2. This study focuses on addressing whether mTORC2 regulates apoptosis, particularly induced by TRAIL (TNFSF10). Using the mTOR kinase inhibitor, PP242, as a research tool, we found that it synergized with TRAIL to augment apoptosis of cancer cells. PP242 reduced the abundance of the short form of c-FLIP (FLIP(S), CFLAR(S)) and survivin (BIRC5). Enforced expression of ectopic FLIP(S), but not survivin, attenuated augmented apoptosis induced by PP242 plus TRAIL. Thus, it is FLIP(S) downregulation that contributes to synergistic induction of apoptosis by PP242 plus TRAIL. PP242 decreased FLIP(S) stability, increased FLIP(S) ubiquitination, and facilitated FLIP(S) degradation. Moreover, knockdown of the E3 ligase Cbl (CBL) abolished PP242-induced FLIP(S) reduction. Thus, PP242 induces Cbl-dependent degradation of FLIP(S), leading to FLIP(S) downregulation. Consistently, knockdown of rictor or mTOR, but not raptor, mimicked PP242 in decreasing FLIP(S) levels and sensitizing cells to TRAIL. Rictor knockdown decreased FLIP(S) stability, whereas enforced expression of rictor stabilized FLIP(S). Moreover, silencing of Cbl abrogated FLIP(S) reduction induced by rictor knockdown. Collectively we conclude that it is mTORC2 inhibition that results in FLIP(S) downregulation and subsequent sensitization of TRAIL-induced apoptosis. Our findings provide the first evidence showing that mTORC2 stabilizes FLIP(S), hence connecting mTORC2 signaling to the regulation of death receptor-mediated apoptosis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.