Everolimus sensitizes Ras-transformed cells to radiation in vitro through the autophagy pathway

Su,Yu-Chieh; Yu,Chih-Chia; Hsu,Fei-Ting; Fu,Shu-Ling; Hwang,Jeng-Jong; Hung,Ling-Chien; Lee,Moon-Sing; Chiou,Wen-Yen; Lin,Hon-Yi; Hung,Shih-Kai

doi:10.3892/ijmm.2014.1927

Everolimus sensitizes Ras-transformed cells to radiation in vitro through the autophagy pathway

Authors:
- Yu-Chieh Su
- Chih-Chia Yu
- Fei-Ting Hsu
- Shu-Ling Fu
- Jeng-Jong Hwang
- Ling-Chien Hung
- Moon-Sing Lee
- Wen-Yen Chiou
- Hon-Yi Lin
- Shih-Kai Hung
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Affiliations: Department of Hematological Oncology, Buddhist Dalin Tzu Chi Hospital, Chiayi 62247, Taiwan, R.O.C., Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei 11221, Taiwan, R.O.C., Institute of Traditional Medicine, National Yang-Ming University, Taipei 11221, Taiwan, R.O.C., Department of Radiation Oncology, Buddhist Dalin Tzu Chi Hospital, Chiayi 62247, Taiwan, R.O.C.
Published online on: September 9, 2014 https://doi.org/10.3892/ijmm.2014.1927
Pages: 1417-1422

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Abstract

Modern radiation therapy strives to minimize injury to organs while increasing the anticancer effects. The present study aimed to investigate the radiosensitizing effects of everolimus and to examine the molecular mechanisms responsible for everolimus‑mediated radiosensitization. Radiation in combination with everolimus (30 nM) sensitized Ras-transformed cells to radiation in vitro. Radiation induced apoptotic markers (sub-G1 cell accumulation, membrane inversion and DNA fragmentation) and treatment with everolimus did not promote radiation-induced apoptosis. However, LC3-II expression increased following combination treatment with everolimus and radiation, and the radiosensitizing effects of everolimus were reversed following transfection with small interfering RNA (siRNA) targeting Beclin 1. In addition, the protein levels of activated S6 kinase 1 (S6K1) were significantly reduced following treatment with everolimus, and the phosphorylation of factor 4E binding protein 1 (4EBP1) was suppressed following combination treatment. Taken together, our data demonstrate that everolimus sensitizes Ras-transformed cells to radiation in vitro. Everolimus-mediated radiosensitization is associated with the autophagy pathway. Thus, everolimus is a novel radiosensitizing agent with potential for use in cancer radiotherapy.

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