Abstract 5549: p53-independent radiosensitization of lung cancer cells by inhibition of mTOR pathway

Abstract

Abstract A high extent of activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and mutations in the p53 gene are involved in lung cancer therapeutic resistance. The mammalian target of rapamycin (mTOR) acts as a downstream effector for Akt and activation of the Akt/mTOR signal is a contributing factor to decreased radiation sensitivity. The aim of this study was to examine whether the effect of rapamycin on radiation sensitivity is affected by cellular p53 gene status in two human non-small cell lung cancer (NSCLC) cell lines with the same genetic background except for their p53 gene status (H1299/wtp53 and H1299/mp53). Cellular radiation sensitivity was evaluated with colony formation assays and apoptosis assays, using Hoechst33342 staining. Rapamycin synergistically enhanced the cytotoxicity of radiation regardless of p53 gene status, and promoted the induction of apoptosis. Moreover, the combined treatment augmented the cytostatic effects of radiation independently of cellular p53 gene status. In agreement with this result, cell cycle analysis by flow cytometry showed increased G1 arrest and suppression of progression to S phase in both cell lines. Western blotting revealed a prominent p53-independent down-regulation of the mTOR signal and pro-survival molecule, cyclin D1 after the combined treatment, suggesting that rapamycin can enhance the effect of radiation through the repression of pro-survival signals and the reduction in the apoptotic threshold. This study indicates that inhibition of the mTOR signal may be a promising strategy for radiosensitization with no relevance to p53 gene status from two aspects of cell lethality and cell growth depression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5549.