title: Elevated expression of AKR1C3 increases resistance of cancer cells to ionizing radiation via modulation of oxidative stress.
abstract: 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.
authors.affiliation: The State Key Laboratory of Natural and Biomimetic Drugs, Beijing, China; The 1st Affiliated Hospital, Peking University, Beijing, China; School of Pharmaceutical Sciences, Peking University, Beijing, China; Tangshan People's Hospital, Hebei, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xiong
authors.affiliation: The State Key Laboratory of Natural and Biomimetic Drugs, Beijing, China; The 1st Affiliated Hospital, Peking University, Beijing, China; School of Pharmaceutical Sciences, Peking University, Beijing, China; Peking Union Medical College Hospital, Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: The State Key Laboratory of Natural and Biomimetic Drugs, Beijing, China; The 1st Affiliated Hospital, Peking University, Beijing, China; School of Pharmaceutical Sciences, Peking University, Beijing, China.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Yu
authors.affiliation: The State Key Laboratory of Natural and Biomimetic Drugs, Beijing, China; The 1st Affiliated Hospital, Peking University, Beijing, China; School of Pharmaceutical Sciences, Peking University, Beijing, China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Li
authors.affiliation: The State Key Laboratory of Natural and Biomimetic Drugs, Beijing, China; The 1st Affiliated Hospital, Peking University, Beijing, China; School of Pharmaceutical Sciences, Peking University, Beijing, China.
authors.forename: Shaoqian
authors.initials: S
authors.lastname: Sun
authors.affiliation: The State Key Laboratory of Natural and Biomimetic Drugs, Beijing, China; School of Pharmaceutical Sciences, Peking University, Beijing, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: The State Key Laboratory of Natural and Biomimetic Drugs, Beijing, China; School of Pharmaceutical Sciences, Peking University, Beijing, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Xia
authors.affiliation: The State Key Laboratory of Natural and Biomimetic Drugs, Beijing, China; School of Pharmaceutical Sciences, Peking University, Beijing, China.
authors.forename: Chuanling
authors.initials: C
authors.lastname: Zhang
authors.affiliation: The State Key Laboratory of Natural and Biomimetic Drugs, Beijing, China; School of Pharmaceutical Sciences, Peking University, Beijing, China.
authors.forename: Qiuchen
authors.initials: Q
authors.lastname: He
authors.affiliation: The State Key Laboratory of Natural and Biomimetic Drugs, Beijing, China; The 1st Affiliated Hospital, Peking University, Beijing, China.
authors.forename: Xianshu
authors.initials: X
authors.lastname: Gao
authors.affiliation: The State Key Laboratory of Natural and Biomimetic Drugs, Beijing, China; School of Pharmaceutical Sciences, Peking University, Beijing, China.
authors.forename: Lihe
authors.initials: L
authors.lastname: Zhang
authors.affiliation: The State Key Laboratory of Natural and Biomimetic Drugs, Beijing, China; School of Pharmaceutical Sciences, Peking University, Beijing, China.
authors.forename: Demin
authors.initials: D
authors.lastname: Zhou
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics* / Q000378:metabolism; D000368:Aged; D000074425:Aldo-Keto Reductase Family 1 Member C3; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics / Q000528:radiation effects; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects*; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000528:radiation effects*; D034622:RNA Interference; D011836:Radiation Tolerance / Q000235:genetics / Q000528:radiation effects; D011839:Radiation, Ionizing; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059467:Transcriptome / Q000528:radiation effects; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000235:genetics / Q000528:radiation effects
chemical_list: D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3