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AMPK-independent autophagy promotes radioresistance of human tumor cells under clinical relevant hypoxia in vitro.
Radiother. Oncol. 116, 409-416 (2015)
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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% O2). 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% O2) and hypoxic (0.01% and 1% O2) 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% O2 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% O2) the stimulation of autophagy mediates resistance of hypoxic tumor cells to ionizing radiation, which is independent of AMPK signaling.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Autophagy ; Clinical Relevant Hypoxia ; Ionizing Radiation ; Solid Tumor Cells
ISSN (print) / ISBN 0167-8140
Zeitschrift Radiotherapy and Oncology
Quellenangaben Band: 116, Heft: 3, Seiten: 409-416
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Radiation Medicine (IRM)