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// Chih-Chia Yu 1, 2, * , Shih-Kai Hung 2, 3, * , Hon-Yi Lin 2, 3 , Wen-Yen Chiou 2, 3 , Moon-Sing Lee 2, 3 , Hui-Fen Liao 4 , Hsien-Bin Huang 1 , Hsu-Chueh Ho 5 and Yu-Chieh Su 6, 7 1 Department of Life Science and Institute of Molecular Biology, National Chung Cheng University, Chia-Yi, Taiwan, R.O.C 2 Department of Radiation Oncology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taiwan, R.O.C 3 School of Medicine, Tzu Chi University, Hualian, Taiwan, R.O.C 4 Department of Biochemical Science and Technology, National Chiayi University, Chia-Yi, Taiwan, R.O.C 5 Department of Otolaryngology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taiwan, R.O.C 6 Division of Hematology and Oncology, E-Da Hospital, Kaohsiung, Taiwan 7 School of Medicine, I-Shou University, Kaohsiung, Taiwan, R.O.C * These authors (Chih-Chia Yu and Shih-Kai Hung) contributed equally to this work Correspondence to: Yu-Chieh Su, email: hepatoma@gmail.com Keywords: PI3K/mTOR pathway, radiation, radiosensitization, radioresistant, oral cancer Received: September 23, 2016 Accepted: June 20, 2017 Published: August 02, 2017 ABSTRACT Radiation therapy (RT) is the current standard adjuvant approach for oral squamous cell carcinoma (OSCC) patients. Radioresistance is a major contributor to radiotherapy failure. In this study, we used patient-derived cells and a radiation-resistant cell line in vitro and in vivo for two purposes: evaluate the anti-tumor effects and understand the mechanisms in the dual PI3K/mTOR signaling pathway regulation of radiosensitization. Our findings indicate that in OML1-R cells, the radioresistance phenotype is associated with activation of the PI3K/AKT/mTOR signaling pathway. Compared to a combination of PI3K or mTOR inhibitors and radiation, dual blockade of the PI3K and mTOR kinases significantly improved radiation efficacy in oral cancer and patient-derived OSCC cells. Dual PI3K/mTOR inhibition enhanced the effect of radiation by inhibiting AKT/mTOR signaling pathways and caused G1 phase arrest, which is associated with downregulation of cyclin D1/CDK4 activity, leading to growth inhibition. In nude mice xenografted with radioresistant OML1-R cells, the combined treatment was also more effective than RT alone in reducing tumor growth. This treatment was also demonstrated to be dependent on the inhibition of protein kinase-dependent S6 kinase pathway and eIF4E-mediated cap-dependent translation. These findings indicate that activation of the PI3K/AKT/mTOR signaling pathway has a role in radioresistance of OSCC. We determined that a PI3K/mTOR inhibitor combined with radiation exhibits synergistic inhibition of the AKT/mTOR axis and induces cell cycle arrest. Our results show the therapeutic potential of drugs targeting the PI3K/AKT/mTOR signaling pathway should be new candidate drugs for radiosensitization in radiotherapy. |
