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Brusatol sensitizes endometrial hyperplasia and cancer to progestin by suppressing NRF2-TET1-AKR1C1-mediated progestin metabolism.
Hu, Meiyan; Sun, Di; Yu, Jing; Fu, Yue; Qin, Zuoshu; Huang, Baozhu; Zhang, Qiuju; Chen, Xiong; Wei, Youheng; Zhu, Huiting; Wang, Yue; Feng, Youji; Zheng, Wenxin; Liao, Hong; Li, Jingjie; Wu, Sufang; Zhang, Zhenbo.
Afiliação
  • Hu M; Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, 200080, China.
  • Sun D; Department of Obstetrics and Gynecology, Zhongshan Hospital Wusong Branch, Fudan University, Shanghai, 201900, China.
  • Yu J; Center for Reproductive Medicine and Fertility Preservation Program, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China.
  • Fu Y; Department of Pathology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 200040, China.
  • Qin Z; Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, 200080, China.
  • Huang B; Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, 200080, China.
  • Zhang Q; Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, 200080, China.
  • Chen X; Department of Obstetrics and Gynecology, Zhongshan Hospital Wusong Branch, Fudan University, Shanghai, 201900, China.
  • Wei Y; Department of Obstetrics and Gynecology, Zhongshan Hospital Wusong Branch, Fudan University, Shanghai, 201900, China.
  • Zhu H; College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, China.
  • Wang Y; Department of Pathology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 200040, China.
  • Feng Y; Department of Obstetrics and Gynecology, Henan Province People's Hospital, Zhengzhou, China.
  • Zheng W; Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, 200080, China.
  • Liao H; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
  • Li J; Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
  • Wu S; Department of Lab Medicine, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 200040, China.
  • Zhang Z; Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, 200080, China. bristlegrassli@aliyun.com.
Lab Invest ; 102(12): 1335-1345, 2022 12.
Article em En | MEDLINE | ID: mdl-36038734
ABSTRACT
Progestin resistance is the main obstacle for the conservative therapy to maintain fertility in women with endometrial cancer. Brusatol was identified as an inhibitor of the NRF2 pathway; however, its impact on progestin resistance and the underlying mechanism remains unclear. Here, we found that brusatol sensitized endometrial cancer to progestin by suppressing NRF2-TET1-AKR1C1-mediated progestin metabolism. Brusatol transcriptionally suppressed AKR1C1 via modifying the hydroxymethylation status in its promoter region through TET1 inhibition. Suppression of AKR1C1 by brusatol resulted in decreased progesterone catabolism and maintained potent progesterone to inhibit endometrial cancer growth. This inhibition pattern has also been found in the established xenograft mouse and organoid models. 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. Our findings suggest that AKR1C1 expression pattern may serve as an important biomarker of progestin resistance in endometrial cancer.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias do Endométrio / Hiperplasia Endometrial Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2022 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias do Endométrio / Hiperplasia Endometrial Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2022 Tipo de documento: Article