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.
Highlights
Endometrial cancer is the sixth leading cause of cancer-related death in women worldwide, with the majority of cases arising in post-menopausal women [1]
We examined the role of NF-E2-related factor 2 (Nrf2) and aldoketo reductase family 1 member C1 (AKR1C1) in the process of progestin resistance with the following approaches: 1) to test the level of Nrf2 and AKR1C1 protein expression in progestin treated endometrial cancer samples; 2) to examine the progestin resistance through up- or down-regulation of Nrf2 and AKR1C1 expression in 2 endometrial cancer cell lines; and 3) to test if the progestin resistance could be reversed by addition of metformin and brusatol, and the effects of these agents on Nrf2 and AKR1C1 expression
Nrf2 and AKR1C1 expression were directly correlated to the progestin resistance
Summary
Endometrial cancer is the sixth leading cause of cancer-related death in women worldwide, with the majority of cases arising in post-menopausal women [1]. Hysterectomy may not be an ideal management choice for those patients when they either have a desire to maintain their fertility or not suitable for surgery. When this happens, progestin treatment as a conservative management is commonly applied. Approximately 30% of such patients fail to respond to progestin therapy [6]. There is no good way to identify or predict which group of patients may respond to the progestin treatment
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