Inhibiting 3βHSD1 to eliminate the oncogenic effects of progesterone in prostate cancer

Zemin Hou; Shengsong Huang; Zejie Mei; Longlong Chen; Jiacheng Guo; Yuanyuan Gao; Qian Zhuang; Xuebin Zhang; Qilong Tan; Tao Yang; Ying Liu; Yongnan Chi; Lifengrong Qi; Ting Jiang; Xuefeng Shao; Yan Wu; Xiaojun Xu; Jun Qin; Ruobing Ren; Huiru Tang; Denglong Wu; Zhenfei Li

doi:10.1016/j.xcrm.2022.100561

Inhibiting 3βHSD1 to eliminate the oncogenic effects of progesterone in prostate cancer

Cell Rep Med. 2022 Mar 15;3(3):100561. doi: 10.1016/j.xcrm.2022.100561.

Authors

Zemin Hou¹, Shengsong Huang², Zejie Mei¹, Longlong Chen³, Jiacheng Guo⁴, Yuanyuan Gao¹, Qian Zhuang¹, Xuebin Zhang¹, Qilong Tan¹, Tao Yang², Ying Liu², Yongnan Chi², Lifengrong Qi⁵, Ting Jiang⁶, Xuefeng Shao⁶, Yan Wu⁷, Xiaojun Xu⁵, Jun Qin⁴, Ruobing Ren^{7

8}, Huiru Tang³, Denglong Wu², Zhenfei Li^{1

2}

Affiliations

¹ State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
² Department of Urology, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China.
³ State Key Laboratory of Genetic Engineering, School of Life Sciences, Human Phenome Institute, Metabonomics and Systems Biology Laboratory at Shanghai International Centre for Molecular Phenomics, Zhongshan Hospital, Fudan University, Shanghai 200438, China.
⁴ CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
⁵ State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, Jiangsu, China.
⁶ Department of Urology, First People's Hospital of Taicang, Taicang, Jiangsu 215400, China.
⁷ Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China.
⁸ Kobilka Institute of Innovative Drug Discovery, School of Life and Health Sciences, the Chinese University of Hong Kong, Shenzhen, Guangdong 518172, China.

Abstract

Prostate cancer continuously progresses following deprivation of circulating androgens originating from the testis and adrenal glands, indicating the existence of oncometabolites beyond androgens. In this study, mass-spectrometry-based screening of clinical specimens and a retrospective analysis on the clinical data of prostate cancer patients indicate the potential oncogenic effects of progesterone in patients. High doses of progesterone activate canonical and non-canonical androgen receptor (AR) target genes. Physiological levels of progesterone facilitate cell proliferation via GATA2. Inhibitors of 3β-hydroxysteroid dehydrogenase 1 (3βHSD1) has been discovered and shown to suppress the generation of progesterone, eliminating its transient and accumulating oncogenic effects. An increase in progesterone is associated with poor clinical outcomes in patients and may be used as a predictive biomarker. Overall, we demonstrate that progesterone acts as an oncogenic hormone in prostate cancer, and strategies to eliminate its oncogenic effects may benefit prostate cancer patients.

Keywords: 3βHSD1; GATA2; abiraterone; biochanin A; drug resistance; oncometabolite; predictive biomarker; progesterone; prostate cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Androgens*
Carcinogenesis
Humans
Male
Progesterone / pharmacology
Prostatic Neoplasms* / drug therapy
Receptors, Androgen / genetics
Retrospective Studies

Substances

Androgens
Receptors, Androgen
Progesterone