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

Yiying Wang, Yue Wang, Zhenbo Zhang, Ji Young Park, Donghui Guo, Hong Liao, Xiaofang Yi, Yu Zheng, Donna Zhang, Setsuko K. Chambers, Wenxin Zheng

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)10363-10372
Number of pages10
JournalOncotarget
Volume7
Issue number9
DOIs
StatePublished - 2016

Keywords

  • AKR1C1
  • Endometrial cancer
  • Nrf2
  • Progestin resistance

ASJC Scopus subject areas

  • Oncology

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