Abstract
Despite considerable efforts, mTOR inhibitors have produced limited success in the clinic. To define the vulnerabilities of mTORC1-addicted cancer cells and to find previously unknown therapeutic targets, we investigated the mechanism of piperlongumine, a small molecule identified in a chemical library screen to specifically target cancer cells with a hyperactive mTORC1 phenotype. Sensitivity to piperlongumine was dependent on its ability to suppress RUVBL1/2-TTT, a complex involved in chromatin remodeling and DNA repair. Cancer cells with high mTORC1 activity are subjected to higher levels of DNA damage stress via c-Myc and displayed an increased dependency on RUVBL1/2 for survival and counteracting genotoxic stress. Examination of clinical cancer tissues also demonstrated that high mTORC1 activity was accompanied by high RUVBL2 expression. Our findings reveal a previously unknown role for RUVBL1/2 in cell survival, where it acts as a functional chaperone to mitigate stress levels induced in the mTORC1-Myc-DNA damage axis.
Original language | English |
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Article number | aay9131 |
Journal | Science Advances |
Volume | 6 |
Issue number | 31 |
DOIs | |
Publication status | Published - 2020 Jul |
Bibliographical note
Funding Information:This research was funded by NIH grant 1RO1CA142805 to S.W.L. and National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (NRF-2017R1C1B1006072) to S.B.
Publisher Copyright:
© 2020 The Authors.
All Science Journal Classification (ASJC) codes
- General