2-Methoxyestradiol enhances radiosensitivity in radioresistant melanoma MDA-MB-435R cells by regulating glycolysis via HIF-1α/PDK1 axis.
HIF-1α 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-1α expression in 435R cells was demonstrated in our recent experiments. Therefore, in the current study, we sought to determine whether selective HIF-1α inhibitors could radiosensitize the 435R cells to X-ray, and to identify the potential mechanisms. Our data demonstrated that inhibition of HIF-1α 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-1α with 2-MeOE2 sensitizes radioresistant melanoma cells 435R to X-ray irradiation through targeting the glycolysis that is regulated by PDK1. Selective inhibitors of HIF-1α and glycolysis are potential drugs to enhance radio-sensitivity of melanoma cells.
Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuchang, Wuhan, Hubei 430071, P.R. China.
Hong
H
Zhao
Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuchang, Wuhan, Hubei 430071, P.R. China.
Huangang
H
Jiang
Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuchang, Wuhan, Hubei 430071, P.R. China.
Zheng
Z
Li
Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuchang, Wuhan, Hubei 430071, P.R. China.
Yafei
Y
Zhuang
Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuchang, Wuhan, Hubei 430071, P.R. China.
Yinyin
Y
Liu
Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuchang, Wuhan, Hubei 430071, P.R. China.
Shuliang
S
Zhou
Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuchang, Wuhan, Hubei 430071, P.R. China.
Youde
Y
Xiao
Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuchang, Wuhan, Hubei 430071, P.R. China.
Conghua
C
Xie
Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuchang, Wuhan, Hubei 430071, P.R. China.
Fuxiang
F
Zhou
Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuchang, Wuhan, Hubei 430071, P.R. China.
Yunfeng
Y
Zhou
D000077584:2-Methoxyestradiol; D017209:Apoptosis / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage / Q000528:radiation effects; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011836:Radiation Tolerance / Q000187:drug effects; D014965:X-Rays
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000631429:PDK1 protein, human; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D004958:Estradiol; D000077584:2-Methoxyestradiol; D017346:Protein Serine-Threonine Kinases