title: Mechanism of progestin resistance in endometrial precancer/cancer through Nrf2-AKR1C1 pathway.
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.
authors.affiliation: Department of Obstetrics and Gynecology, Henan Province People's Hospital, Zhengzhou, China.|Department of Pathology, University of Arizona College of Medicine, Tucson, AZ, USA.|Department of Obstetrics and Gynecology, University of Arizona College of Medicine, Tucson, AZ, USA.
authors.forename: Yiying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, Henan Province People's Hospital, Zhengzhou, China.|Department of Pathology, University of Arizona College of Medicine, Tucson, AZ, USA.|Department of Obstetrics and Gynecology, University of Arizona College of Medicine, Tucson, AZ, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathology, University of Arizona College of Medicine, Tucson, AZ, USA.|Reproductive Medicine, Department of Obstetrics and Gynecology, Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Zhenbo
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Pathology, University of Arizona College of Medicine, Tucson, AZ, USA.|Department of Pathology, Kyungpook National University, School of Medicine, Daegu, Korea.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Park
authors.affiliation: Department of Obstetrics and Gynecology, Tianjin Gynecologic and Obstetrics Central Hospital, Tianjin, China.
authors.forename: Donghui
authors.initials: D
authors.lastname: Guo
authors.affiliation: Department of Pathology, University of Arizona College of Medicine, Tucson, AZ, USA.|Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Liao
authors.affiliation: Department of Obstetrics and Gynecology, Fudan University, Shanghai, China.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Yi
authors.affiliation: Shanghai Jiai Genetics and IVF Institute, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Obstetrics and Gynecology, University of Arizona College of Medicine, Tucson, AZ, USA.|Arizona Cancer Center, University of Arizona, Tucson, AZ, USA.
authors.forename: Setsuko K
authors.initials: SK
authors.lastname: Chambers
authors.affiliation: Department of Pathology, University of Arizona College of Medicine, Tucson, AZ, USA.|Department of Obstetrics and Gynecology, University of Arizona College of Medicine, Tucson, AZ, USA.|Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.|Arizona Cancer Center, University of Arizona, Tucson, AZ, USA.
authors.forename: Wenxin
authors.initials: W
authors.lastname: Zheng
mesh_terms: D015089:20-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D014408:Biomarkers, Tumor; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D004717:Endometrium / Q000378:metabolism; D005260:Female; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D008687:Metformin / Q000494:pharmacology; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D011372:Progestins / Q000627:therapeutic use*; D036702:Quassins / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D011372:Progestins; D036702:Quassins; D034741:RNA, Small Interfering; C020237:brusatol; D008687:Metformin; D017258:Medroxyprogesterone Acetate; D015089:20-Hydroxysteroid Dehydrogenases; C115140:3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase
keywords: AKR1C1; Nrf2; endometrial cancer; progestin resistance
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