Elevated expression of AKR1C3 increases resistance of cancer cells to ionizing radiation via modulation of oxidative stress

• Published in: PloS one 2014-11, Vol.9 (11), p.e111911-e111911
• Main Authors: Xiong, Wei, Zhao, Jing, Yu, Hongliang, Li, Xiaoying, Sun, Shaoqian, Li, Yi, Xia, Qing, Zhang, Chuanling, He, Qiuchen, Gao, Xianshu, Zhang, Lihe, Zhou, Demin
• Format: Article
• Language: English
• Subjects: 3-Hydroxysteroid Dehydrogenases - genetics; 3-Hydroxysteroid Dehydrogenases - metabolism; Aged; Aldo-keto reductase; Aldo-Keto Reductase Family 1 Member C3; Analysis; Animal tissues; Animals; Antioxidants; Biology and Life Sciences; Biomarkers; Blotting, Western; Breast cancer; Cancer; Cancer cells; Cancer therapies; Cancer treatment; Cell division; Cell Line, Tumor; Cell Proliferation - genetics; Cell Proliferation - radiation effects; Chemical inhibitors; Damage accumulation; Dehydrogenases; Deoxyribonucleic acid; Development and progression; DNA; DNA damage; Drugs; Enzymes; Esophageal cancer; Esophageal carcinoma; Esophageal Neoplasms - genetics; Esophageal Neoplasms - metabolism; Esophageal Neoplasms - pathology; Esophagus; Etiology; Female; Gene Expression Regulation, Neoplastic - radiation effects; Health aspects; Hospitals; Human tissues; Humans; Hydroxyprostaglandin Dehydrogenases - genetics; Hydroxyprostaglandin Dehydrogenases - metabolism; I.R. radiation; Immunohistochemistry; Ionizing radiation; Laboratories; Male; Medical research; Medicine and Health Sciences; Metabolism; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Oligonucleotide Array Sequence Analysis; Oxidation resistance; Oxidative stress; Oxidative Stress - radiation effects; Pharmaceutical sciences; Prostate cancer; R&D; Radiation; Radiation therapy; Radiation Tolerance - genetics; Radiation Tolerance - radiation effects; Radiation, Ionizing; Radioresistance; Research & development; Retrospective Studies; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; RNA-mediated interference; Surgery; Transcriptome - radiation effects; Transplantation, Heterologous; Tumor Burden - genetics; Tumor Burden - radiation effects; Tumor cells; Tumors; Xenografts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0111911

With the aim to elucidate the etiology of radioresistance, we explored the genetic alterations in non-radioresistant vs. resistant esophageal cancer cells acquired by long-term fractionated radiation. We found AKR1C3, an aldo-keto reductase expressed seldom in most human tissues, expressed higher in radioresistance-acquired cells. Suppression of AKR1C3 via RNAi or its chemical inhibitors restored the sensitivity of the acquired tumor cells and xenograft BALB/c nude mice to ionizing radiation (IR). Cellular monitoring of the oxidative stress in the AKR1C3-elevated cells indicated that IR-induced ROS accumulation and the concomitant DNA damage was significantly alleviated, and such protective consequence disappeared upon AKR1C3 knockdown. These findings uncover the potential involvement of AKR1C3 in removal of cellular ROS and explain, at least partially, the acquired radioresistance by AKR1C3 overexpression. A retrospective analysis of esophageal carcinomas also indicated a significant expression of AKR1C3 in radio-resistant but not radio-sensitive surgical samples. Our study may provide a potential biomarker for predicting prognosis of radiotherapy and even direct a targeted therapy for esophageal cancer and other tumors.