Abstract
Inhibition of mammalian target of rapamycin-complex 1 (mTORC1) induces activation of Akt. Because Akt activity mediates the repair of ionizing radiation-induced DNA double-strand breaks (DNA-DSBs) and consequently the radioresistance of solid tumors, we investigated whether dual targeting of mTORC1 and Akt impairs DNA-DSB repair and induces radiosensitization. Combining mTORC1 inhibitor rapamycin with ionizing radiation in human non-small cell lung cancer (NSCLC) cells (H661, H460, SK-MES-1, HTB-182, A549) and in the breast cancer cell line MDA-MB-231 resulted in radiosensitization of H661 and H460 cells (responders), whereas only a very slight effect was observed in A549 cells, and no effect was observed in SK-MES-1, HTB-182 or MDA-MB-231 cells (non-responders). In responder cells, rapamycin treatment did not activate Akt1 phosphorylation, whereas in non-responders, rapamycin mediated PI3K-dependent Akt activity. Molecular targeting of Akt by Akt inhibitor MK2206 or knockdown of Akt1 led to a rapamycin-induced radiosensitization of non-responder cells. Compared to the single targeting of Akt, the dual targeting of mTORC1 and Akt1 markedly enhanced the frequency of residual DNA-DSBs by inhibiting the non-homologous end joining repair pathway and increased radiation sensitivity. Together, lack of radiosensitization induced by rapamycin was associated with rapamycin-mediated Akt1 activation. Thus, dual targeting of mTORC1 and Akt1 inhibits repair of DNA-DSB leading to radiosensitization of solid tumor cells.
Highlights
The mammalian target of rapamycin pathway plays a major role in the regulation of cell growth, proliferation and survival [1, 2]
Physiological activation of the PI3K/Akt/mammalian target of rapamycin (mTOR) complex-1 (mTORC1) pathway is regulated by a negative feedback mechanism, whereby S6K1-mediated phosphorylation leads to inactivation of insulin receptor substrate 1 (IRS1) and to decreased PI3K/Akt activity [11, 12]
This effect was further analyzed in five non-small cell lung cancer (NSCLC) cell lines: A549, SK-MES-1, HTB-182, H661 and H460
Summary
The mammalian target of rapamycin (mTOR) pathway plays a major role in the regulation of cell growth, proliferation and survival [1, 2]. S6K1 and 4EBP1 are downstream signaling elements of mTORC1 that promote tumor cell growth by stimulating protein synthesis [2, 3]. An allosteric mTORC1 inhibitor, and its analogs inhibit mTORC1 kinase activity. The limited effectiveness of mTORC1 inhibitors may be due to a lack of complete inhibition of mTORC1 [9] or, more importantly, it may be due to rapamycin-mediated activation of the PI3K/Akt pathway [10]. The inhibition of mTORC1 by rapamycin abrogates this feedback regulation, leading to PI3K-dependent Akt phosphorylation [13, 14]
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