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DNA damage-induced S and G2/M cell cycle arrest requires mTORC2-dependent regulation of Chk1.

Selvarajah, J; Elia, A; Carroll, VA; Moumen, A (2015) DNA damage-induced S and G2/M cell cycle arrest requires mTORC2-dependent regulation of Chk1. Oncotarget, 6 (1). pp. 427-440. ISSN 1949-2553 https://doi.org/10.18632/oncotarget.2813
SGUL Authors: Carroll, Veronica Selvarajah, Jogitha

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Abstract

mTOR signalling is commonly dysregulated in cancer. Concordantly, mTOR inhibitors have demonstrated efficacy in a subset of tumors and are in clinical trials as combination therapies. Although mTOR is associated with promoting cell survival after DNA damage, the exact mechanisms are not well understood. Moreover, since mTOR exists as two complexes, mTORC1 and mTORC2, the role of mTORC2 in cancer and in the DNA damage response is less well explored. Here, we report that mTOR protein levels and kinase activity are transiently increased by DNA damage in an ATM and ATR-dependent manner. We show that inactivation of mTOR with siRNA or pharmacological inhibition of mTORC1/2 kinase prevents etoposide-induced S and G2/M cell cycle arrest. Further results show that Chk1, a key regulator of the cell cycle arrest, is important for this since ablation of mTOR prevents DNA damage-induced Chk1 phosphorylation and decreases Chk1 protein production. Furthermore, mTORC2 was essential and mTORC1 dispensable, for this role. Importantly, we show that mTORC1/2 inhibition sensitizes breast cancer cells to chemotherapy. Taken together, these results suggest that breast cancer cells may rely on mTORC2-Chk1 pathway for survival and provide evidence that mTOR kinase inhibitors may overcome resistance to DNA-damage based therapies in breast cancer.

Item Type: Article
Additional Information: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: mTORC1, mTORC2, Chk1, DNA damage response, cell cycle arrest, breast cancer
SGUL Research Institute / Research Centre: Academic Structure > Institute of Medical & Biomedical Education (IMBE)
Academic Structure > Institute of Medical & Biomedical Education (IMBE) > Centre for Biomedical Education (INMEBE)
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cell Sciences (INCCCS)
Journal or Publication Title: Oncotarget
ISSN: 1949-2553
Language: eng
Dates:
DateEvent
1 January 2015Published
15 November 2014Published Online
14 November 2014Accepted
Projects:
Project IDFunderFunder ID
082609/A/07/ZWellcome TrustUNSPECIFIED
PubMed ID: 25460505
Web of Science ID: WOS:000352065200034
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/107402
Publisher's version: https://doi.org/10.18632/oncotarget.2813

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