期刊
RADIOTHERAPY AND ONCOLOGY
卷 116, 期 3, 页码 409-416出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.radonc.2015.08.012
关键词
Clinical relevant hypoxia; Autophagy; Ionizing radiation; Solid tumor cells
资金
- Deutsche Forschungsgemeinschaft [SFB-773 TP-B2, Ro 572/7-1, SFB773 TP-Z2]
- DFG-Graduate School [SFB773]
- [SFB824/II]
Background and purpose: Blocking of the autophagy-signaling has the potential to improve cancer therapy. In the present study, the role of autophagy for radioresistance of human tumor cells was tested under clinically relevant hypoxia (1% O-2). Materials and methods: Non-small cell lung cancer cell lines A549 and H460, head and neck squamous cell carcinoma FaDu, colon carcinoma cell line HCT116 and mouse-embryo-fibroblasts were analyzed under normoxic (21% O-2) and hypoxic (0.01% and 1% O-2) conditions with respect to clonogenic cell survival and hypoxia-induced autophagy. Immunofluorescence and electron microscopy were used to monitor the autophagy process and Western blotting of LC3, AMPK, and BNIP3 was applied to analyze autophagy signaling. Results: Clinically relevant hypoxia stimulated autophagy in tumor cells as indicated by enhanced LC3-I to LC3-II conversion. Furthermore, hypoxia stimulated autophagy was approved by Immunofluorescence staining and electron-microscopy analysis of autophagosome vacuoles. Preconditioning of tumor cells to moderate-hypoxia increased their radioresistance that was significantly reversed following pretreatment with autophagy inhibitor, chloroquine. Using siRNA against AMPK as well as AMPK deficient cells, autophagy stimulation by 1% O-2 was shown to be AMPK-independent. However, a correlation between the expression of BNIP3 and autophagy-stimulation was observed under this condition. Conclusion: Under clinically relevant hypoxia (1% O-2) the stimulation of autophagy mediates resistance of hypoxic tumor cells to ionizing radiation, which is independent of AMPK signaling. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
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