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.
Highlights
Mammalian target of rapamycin is a serine-threonine kinase of the phosphoinositide 3-kinaserelated kinase (PIKK) family which plays a central role in cell growth and it is commonly dysregulated in cancer [1,2,3,4,5,6]
Since its discovery as the target of rapamycin, Mammalian target of rapamycin (mTOR) has been identified as a crucial mediator of protein synthesis, cell growth, and metabolism. mTORC1 is important for relaying signals to the cell machinery in response to DNA damage
As mTOR is a key regulator of cell cycle progression from G1 to S phase [27], we investigated whether mTOR promotes cell survival following DNA damage by regulating cell cycle arrest, which would allow more time for DNA repair
Summary
Mammalian target of rapamycin (mTOR) is a serine-threonine kinase of the phosphoinositide 3-kinaserelated kinase (PIKK) family which plays a central role in cell growth and it is commonly dysregulated in cancer [1,2,3,4,5,6]. Other members of this family include ATM, ATR and DNA-PKcs, which have well established roles in DNA damage response signalling. Two groups have identified that mTORC1 regulates the DNA damage response www.impactjournals.com/oncotarget through the upregulation of FANCD2 gene expression, a key protein involved in the repair of DNA double-strand breaks [22, 23]
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