|Title||mTORC1-Driven Tumor Cells Are Highly Sensitive to Therapeutic Targeting by Antagonists of Oxidative Stress.|
|Publication Type||Journal Article|
|Year of Publication||2016|
|Authors||Li J, Shin S, Sun Y, Yoon S-O, Li C, Zhang E, Yu J, Zhang J, Blenis J|
|Date Published||2016 08 15|
|Keywords||Animals, Antineoplastic Agents, Antioxidants, Apoptosis, Cell Line, Tumor, Drug Screening Assays, Antitumor, Female, Fibroblasts, Gene Knockdown Techniques, High-Throughput Screening Assays, Humans, Immunohistochemistry, In Situ Nick-End Labeling, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, SCID, Microscopy, Confocal, Microscopy, Electron, Transmission, Multiprotein Complexes, Oxidative Stress, Polymerase Chain Reaction, Reactive Oxygen Species, Sirolimus, TOR Serine-Threonine Kinases, Tumor Suppressor Proteins|
mTORC1 is a central signaling node in controlling cell growth, proliferation, and metabolism that is aberrantly activated in cancers and certain cancer-associated genetic disorders, such as tuberous sclerosis complex (TSC) and sporadic lymphangioleiomyomatosis. However, while mTORC1-inhibitory compounds (rapamycin and rapalogs) attracted interest as candidate therapeutics, clinical trials have not replicated the promising findings in preclinical models, perhaps because these compounds tend to limit cell proliferation without inducing cell death. In seeking to address this issue, we performed a high-throughput screen for small molecules that could heighten the cytotoxicity of mTORC1 inhibitors. Here we report the discovery that combining inhibitors of mTORC1 and glutamate cysteine ligase (GCLC) can selectively and efficiently trigger apoptosis in Tsc2-deficient cells but not wild-type cells. Mechanistic investigations revealed that co-inhibition of mTORC1 and GCLC decreased the level of the intracellular thiol antioxidant glutathione (GSH), thereby increasing levels of reactive oxygen species, which we determined to mediate cell death in Tsc2-deficient cells. Our findings offer preclinical proof of concept for a strategy to selectively increase the cytotoxicity of mTORC1 inhibitors as a therapy to eradicate tumor cells marked by high mTORC1 signaling, based on cotargeting a GSH-controlled oxidative stress pathway. Cancer Res; 76(16); 4816-27. ©2016 AACR.
|Alternate Journal||Cancer Res.|
|PubMed Central ID||PMC5518474|
|Grant List||R01 DK098331 / DK / NIDDK NIH HHS / United States |
R01 GM051405 / GM / NIGMS NIH HHS / United States
R01 HL098216 / HL / NHLBI NIH HHS / United States
R01 HL121266 / HL / NHLBI NIH HHS / United States
mTORC1-Driven Tumor Cells Are Highly Sensitive to Therapeutic Targeting by Antagonists of Oxidative Stress.
Submitted by job2075 on September 11, 2018 - 4:25pm