Mechanism of progestin resistance in endometrial precancer/cancer through Nrf2-AKR1C1 pathway
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Yiying Wang1,2,3, Yue Wang1,2,3, Zhenbo Zhang2,4, Ji-Young Park2,5, Donghui Guo6, Hong Liao2,7, Xiaofang Yi8, Yu Zheng9, Donna Zhang10, Setsuko K. Chambers3,12, Wenxin Zheng2,3,11,12
1Department of Obstetrics and Gynecology, Henan Province People’s Hospital, Zhengzhou, China
2Department of Pathology, University of Arizona College of Medicine, Tucson, AZ, USA
3Department of Obstetrics and Gynecology, University of Arizona College of Medicine, Tucson, AZ, USA
4Reproductive Medicine, Department of Obstetrics and Gynecology, Shanghai First People’s Hospital, Shanghai Jiaotong University, Shanghai, China
5Department of Pathology, Kyungpook National University, School of Medicine, Daegu, Korea
6Department of Obstetrics and Gynecology, Tianjin Gynecologic and Obstetrics Central Hospital, Tianjin, China
7Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
8Department of Obstetrics and Gynecology, Fudan University, Shanghai, China
9Shanghai Jiai Genetics and IVF Institute, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, China
10Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, USA
11Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
12Arizona Cancer Center, University of Arizona, Tucson, AZ, USA
Zhenbo Zhang, e-mail: [email protected]
Wenxin Zheng, e-mail: [email protected]
Keywords: Nrf2, AKR1C1, endometrial cancer, progestin resistance
Received: July 12, 2015 Accepted: January 01, 2016 Published: January 25, 2016
Progestin resistance is a main obstacle for endometrial precancer/cancer conservative therapy. Therefore, biomarkers to predict progestin resistance and studies to gain a more detailed understanding of the mechanism are needed. The antioxidant Nrf2-AKR1C1 signal pathway exerts chemopreventive activity. However whether it plays a role in progestin resistance has not been explored. In this study, elevated levels of AKR1C1 and Nrf2 were found in progestin-resistant endometrial epithelia, but not in responsive endometrial glands. Exogenous overexpression of Nrf2/AKR1C1 resulted in progestin resistance. Inversely, silencing of Nrf2 or AKR1C1 rendered endometrial cancer cells more susceptible to progestin treatment. Moreover, medroxyprogesterone acetate withdrawal resulted in suppression of Nrf2/AKR1C1 expression accompanied by a reduction of cellular proliferative activity. In addition, brusatol and metformin overcame progestin resistance by down-regulating Nrf2/AKR1C1 expression. Our findings suggest that overexpression of Nrf2 and AKR1C1 in endometrial precancer/cancer may be part of the molecular mechanisms underlying progestin resistance. If validated in a larger cohort, overexpression of Nrf2 and AKR1C1 may prove to be useful biomarkers to predict progestin resistance. Targeting the Nrf2/AKR1C1 pathway may represent a new therapeutic strategy for treatment of endometrial hyperplasia/cancer.
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