In:
Science Advances, American Association for the Advancement of Science (AAAS), Vol. 6, No. 31 ( 2020-07-31)
Kurzfassung:
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.
Materialart:
Online-Ressource
ISSN:
2375-2548
DOI:
10.1126/sciadv.aay9131
Sprache:
Englisch
Verlag:
American Association for the Advancement of Science (AAAS)
Publikationsdatum:
2020
ZDB Id:
2810933-8