Journal
INTERNATIONAL JOURNAL OF ONCOLOGY
Volume 50, Issue 5, Pages 1531-1540Publisher
SPANDIDOS PUBL LTD
DOI: 10.3892/ijo.2017.3924
Keywords
melanoma; HIF-1 alpha; glycolysis; radiosensitivity; 2-MeOE2; dichloroacetate; metabolism
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HIF-1 alpha overexpression is associated with radio resistance of various cancers. A radioresistant human melanoma cell model MDA-MB-435R (435R) was established by us previously. Compared with the parental cells MDA-MB-435 (435S), an elevated level of HIF-1 alpha expression in 435R cells was demonstrated in our recent experiments. Therefore, in the current study, we sought to determine whether selective HIF-1 alpha inhibitors could radiosensitize the 435R cells to X-ray, and to identify the potential mechanisms. Our data demonstrated that inhibition of HIF-1 alpha with 2-methoxyestradiol (2-MeOE2) significantly enhanced radiosensitivity of 435R cells. 2-MeOE2 increased DNA damage and ratio of apoptosis cells induced by irradiation. Whereas, cell proliferation and the expression of pyruvate dehydrogenase kinase 1 (PDK1) were decreased after 2-MeOE2 treatment. The change of expression of GLUT1, LDHA and the cellular ATP level and extracellular lactate production indicates that 2-MeOE2 suppressed glycolytic state of 435R cells. In addition, the radioresistance, glycolytic state and cell proliferation of 435R cells were also decreased after inhibiting pyruvate dehydrogenase kinase 1 (PDK1) with dichloroacetate (DCA). DCA could also increase DNA damage and ratio of apoptotic cells induced by irradiation. These results also suggest that inhibition of HIF-1 alpha with
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