PI3K/mTOR pathway inhibition overcomes radioresistance via suppression of the HIF1-α/VEGF pathway in endometrial cancer.
Radiation therapy is a key therapeutic strategy for endometrial carcinomas. However, biomarkers that predict radiosensitivity and drugs to enhance this sensitivity have not yet been established. We aimed to investigate the roles of TP53 and MAPK/PI3K pathways in endometrial carcinomas and to identify appropriate radiosensitizing therapeutics. D10 values (the irradiating dose required to reduce a cell population by 90%) were determined in eight endometrial cancer cell lines with known mutational statuses for TP53, PIK3CA, and KRAS. Cells were exposed to ionizing radiation (2-6Gy) and either a dual PI3K/mTOR inhibitor (NVP-BEZ235) or a MEK inhibitor (UO126), and their radiosensitizing effects were evaluated using clonogenic assays. The effects of silencing hypoxia-inducible factor-1 α (HIF-1α) expression with small interfering RNAs (siRNAs) were evaluated following exposure to ionizing radiation (2-3Gy). D10 values ranged from 2.0 to 3.1Gy in three cell lines expressing wild-type TP53 or from 3.3 to more than 6.0Gy in five cell lines expressing mutant TP53. NVP-BEZ235, but not UO126, significantly improved radiosensitivity through the suppression of HIF-1α/vascular endothelial growth factor-A expression. HIF-1α silencing significantly increased the induction of the sub-G1 population by ionizing radiation. Our study data suggest that TP53 mutation and PI3K pathway activation enhances radioresistance in endometrial carcinomas and that targeting the PI3K/mTOR or HIF-1α pathways could improve radiosensitivity.
Department of Obstetrics and Gynaecology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo 113-8655, Japan.
Aki
A
Miyasaka
Department of Obstetrics and Gynaecology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo 113-8655, Japan. Electronic address: katsutoshi-tky@umin.ac.jp.
Katsutoshi
K
Oda
Department of Obstetrics and Gynaecology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo 113-8655, Japan.
Yuji
Y
Ikeda
Department of Obstetrics and Gynaecology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo 113-8655, Japan.
Kenbun
K
Sone
Department of Obstetrics and Gynaecology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo 113-8655, Japan.
Tomohiko
T
Fukuda
Department of Obstetrics and Gynaecology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo 113-8655, Japan.
Kanako
K
Inaba
Department of Obstetrics and Gynaecology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo 113-8655, Japan.
Chinami
C
Makii
Laboratory of Molecular Radiology, Centre for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Atsushi
A
Enomoto
Laboratory of Molecular Radiology, Centre for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Noriko
N
Hosoya
Department of Obstetrics and Gynaecology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo 113-8655, Japan.
Michihiro
M
Tanikawa
Department of Obstetrics and Gynaecology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo 113-8655, Japan.
Yuriko
Y
Uehara
Department of Obstetrics and Gynaecology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo 113-8655, Japan.
Takahide
T
Arimoto
Kanagawa Health Service Association, Kanagawa, Japan.
Hiroyuki
H
Kuramoto
Department of Obstetrics and Gynaecology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo 113-8655, Japan.
Osamu
O
Wada-Hiraike
Laboratory of Molecular Radiology, Centre for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Kiyoshi
K
Miyagawa
Department of Obstetrics and Gynaecology, National Centre for Global Health and Medicine, Tokyo, Japan.
Tetsu
T
Yano
Department of Obstetrics and Gynaecology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo 113-8655, Japan.
Kei
K
Kawana
Department of Obstetrics and Gynaecology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo 113-8655, Japan.
Yutaka
Y
Osuga
Department of Obstetrics and Gynaecology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo 113-8655, Japan.
Tomoyuki
T
Fujii
D002070:Butadienes / Q000494:pharmacology; D018269:Carcinoma, Endometrioid / Q000188:drug therapy / Q000532:radiotherapy; D045744:Cell Line, Tumor; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D016158:Genes, p53; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines / Q000494:pharmacology; D011836:Radiation Tolerance / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism
D002070:Butadienes; D004791:Enzyme Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007093:Imidazoles; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; D058570:TOR Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A; C497442:HIF1A protein, human; C113580:U 0126; C467484:VEGFA protein, human; C546842:MTOR protein, human; C531198:dactolisib
Endometrial carcinoma; Hypoxia-inducible factor-1α; Phosphatidylinositol 3-kinase; Radiosensitivity; TP53