Radioresistance is a major challenge during the treatment of breast cancer. A further understanding of the mechanisms of radioresistance could provide strategies to address this challenge. In our study, we compared the expression of miR- Breast cancer is the most common cancer in women worldwide. 1 Radiotherapy is an important part of the treatment in most patients receiving breast-conserving surgery and displays significant clinical benefits, such as decreasing the risk of local recurrence and reducing the risk of mortality due to breast cancer. 2 However, for certain subtypes of breast cancer (e.g., basal-like), the local and regional control remains unsatisfactory. A major reason for this failure in treatment may be due to its radioresistance. 3-5 Therefore, understanding the molecular mechanisms involved in the radioresistance of breast tumors may lead to improved clinical outcomes.Autophagy is a cellular process that involves selfdegradation and recycling of macromolecules and cellular organelles. 6,7 It is, in most circumstances, a prosurvival mechanism under stressful conditions. Autophagy has been implicated in a variety of human diseases. [7][8][9] Similar to the situation in normal cells, autophagy is also critical for tumor cells to survive stressful conditions, and thus has been implicated in tumor resistance to chemotherapy and radiotherapy. [10][11][12][13] MicroRNAs (miRNAs) regulate a variety of biological processes, including cell proliferation, differentiation and invasion. 14 Dysregulation of miRNAs has been reported to contribute to cancer, 15,16 and implicated in chemoresistance and radioresistance via modulation of autophagy. 10,13 Such findings are not surprising considering the fact that miRNAs are key regulators of autophagy. 17 The miR-200 family is involved in the self-renewal of cancer stem cells, 18 epithelial-to-mesenchymal transition (EMT) 19,20 and chemosensitivity. 21 Recent studies indicated that miR-200c, the prevailing member of the miR-200 family, 19,20,22,23 could sensitize cancer cells to radiation by targeting TBK1 and VEGF-VEGFR2, despite the unspecified relationship between miR-200c and autophagy. 24,25 The results from our study showed that miR-200c could sensitize breast cancer cells to radiation via a mechanism associated with inhibition of irradiation-induced autophagy.

Although combined chemoradiotherapy has provided considerable improvements for nasopharyngeal carcinoma (NPC), recurrence and metastasis are still frequent. The PI3K/Akt/mTOR pathway plays a critical role in tumor formation and tumor cell survival after radiation-induced DNA damage. In the present study, we evaluated whether inhibition of PI3K/mTOR by two novel dual inhibitors, GSK2126458 and PKI-587, could suppress tumor progression and sensitize NPC cells to radiation. Four NPC cell lines (CNE-1, CNE-2, 5-8F, and 6-10B) were used to analyze the effects of GSK216458 and PKI-587 on cell proliferation, migration, invasion, clonogenic survival, amount of residual g-H2AX foci, cell cycle, and apoptosis after radiation. A 5-8F xenograft model was used to evaluate the in vivo effects of the two compounds in combination with ionizing radiation (IR).Both GSK216458 and PKI-587 effectively inhibited cell proliferation and motility in NPC cells and suppressed phosphorylation of Akt, mTOR, S6, and 4EBP1 proteins in a concentration-and time-dependent manner. Moreover, both compounds sensitized NPC cells to IR by increasing DNA damage, enhancing G 2 -M cellcycle delay, and inducing apoptosis. In vivo, the combination of IR with GSK2126458 or PKI-587 significantly inhibited tumor growth. Antitumor effect was correlated with induction of apoptosis and suppression of the phosphorylation of mTOR, Akt, and 4EBP1. These new findings suggest the usefulness of PI3K/mTOR dual inhibition for antitumor and radiosensitizing. The combination of IR with a dual PI3K/mTOR inhibitor, GSK2126458 or PKI-587, might be a promising therapeutic strategy for NPC. Mol Cancer Ther; 14(2); 429-39. Ó2014 AACR.