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Oncotarget. 2016 Mar 1;7(9):10363-72. doi: 10.18632/oncotarget.7004.

Mechanism of progestin resistance in endometrial precancer/cancer through Nrf2-AKR1C1 pathway.

Wang Y1,2,3, Wang Y1,2,3, Zhang Z2,4, Park JY2,5, Guo D6, Liao H2,7, Yi X8, Zheng Y9, Zhang D10, Chambers SK3,11, Zheng W2,3,12,11.

Author information

1
Department of Obstetrics and Gynecology, Henan Province People's Hospital, Zhengzhou, China.
2
Department of Pathology, University of Arizona College of Medicine, Tucson, AZ, USA.
3
Department of Obstetrics and Gynecology, University of Arizona College of Medicine, Tucson, AZ, USA.
4
Reproductive Medicine, Department of Obstetrics and Gynecology, Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai, China.
5
Department of Pathology, Kyungpook National University, School of Medicine, Daegu, Korea.
6
Department of Obstetrics and Gynecology, Tianjin Gynecologic and Obstetrics Central Hospital, Tianjin, China.
7
Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.
8
Department of Obstetrics and Gynecology, Fudan University, Shanghai, China.
9
Shanghai Jiai Genetics and IVF Institute, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, China.
10
Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, USA.
11
Arizona Cancer Center, University of Arizona, Tucson, AZ, USA.
12
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Abstract

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.

KEYWORDS:

AKR1C1; Nrf2; endometrial cancer; progestin resistance

PMID:
26824415
PMCID:
PMC4891125
DOI:
10.18632/oncotarget.7004
[Indexed for MEDLINE]
Free PMC Article

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