Brusatol sensitizes endometrial hyperplasia and cancer to progestin by suppressing NRF2-TET1-AKR1C1-mediated progestin metabolism
| Autor: | Zuoshu Qin, Huiting Zhu, Qiuju Zhang, Youji Feng, Yue Wang, Meiyan Hu, Jing Yu, Wenxin Zheng, Yue Fu, Youheng Wei, Hong Liao, Jingjie Li, Baozhu Huang, Sufang Wu, Di Sun, Zhenbo Zhang, Xiong Chen |
|---|---|
| Rok vydání: | 2022 |
| Předmět: |
medicine.drug_class
AKR1C1 NF-E2-Related Factor 2 Pathology and Forensic Medicine Mixed Function Oxygenases Mice Proto-Oncogene Proteins Medicine Humans Animals Molecular Biology Progesterone business.industry Cancer Cell Biology Metabolism medicine.disease Endometrial hyperplasia Endometrial Neoplasms DNA-Binding Proteins Endometrial Hyperplasia Cancer research Female Progestins business Progestin hormones hormone substitutes and hormone antagonists |
| Zdroj: | Laboratory investigation; a journal of technical methods and pathology. 102(12) |
| ISSN: | 1530-0307 |
| Popis: | BackgroundProgestin resistance is the main obstacle for the conservative therapy to maintain fertility in women with endometrial hyperplasia and cancer. Up to 30% of endometrial cancers fail to respond to progestin, a rate that has not significantly changed due to the lack of a detailed understanding of progestin resistance.MethodsCell Counting Kit-8 (CCK-8) assays were used to detect the synergistic effects of brusatol in combination with progestin. Using commercial kits, the conversion of progestin to 20α-dihydroxyprogesterone following btusatol treatment or AKR1C1 silence was investigated. The correlation betwwen AKR1C1 expression profile and prgestin response was further analyzed in paired endometrial hyperplasia and cancer samples from the same individuals before and after progestin therapy. The effects of brusatol-mediated reversal of progestin resistance was explored in both mouse xenograft and human organoid models. DNA dot blot, HMeDIP, and dural-luciferase reporter assays were performed to uncover the mechanism through which brusatol inhibits AKR1C1 and sensitizes endometrial hyperplasia and cancer to progestin.ResultsBrusatol sensitizes endometrial cancer cell to progestin by downregulating the expression of Nrf2 and its target AKR1C1. Increased AKR1C1 facilitated production of 20-α-dihydroxyprogeserone and was associated with declined progesterone. Suppression of AKR1C1 by brusatol resulted in decreased progesterone catabolism and maintained potent progesterone to inhibit endometrial cancer growth. Aberrant overexpression of AKR1C1 was found in paired endometrial hyperplasia and cancer samples from the same individuals with progestin resistance, whereas attenuated or loss of AKR1C1 was observed in post-treatment samples with well progestin response as compared with paired pre-treatment tissues. Tet1 was identified as a novel Nrf2 target gene. It in turn upregulated AKR1C1 expression by increasing hydroxymethylation levels in its promoter regions. ConclusionsWe found that Nrf2-Tet1-AKR1C1 axis plays an essential role in progestin resistance, and brusatol sensitizes endometrial hyperplasia and cancer to progestin by suppressing Nrf2-Tet1-AKR1C1-mediated progestin metabolism. Our findings suggest that AKR1C1 expression pattern may serve as an important biomarker of progestin resistance in endometrial hyperplasia and cancer . |
| Databáze: | OpenAIRE |
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