Management of prostate cancer by targeting 3βHSD1 after enzalutamide and abiraterone treatment

  • Cell Rep Med. 2022 May 17;3(5):100608. doi: 10.1016/j.xcrm.2022.100608.
Zejie Mei  1 ,  Tao Yang  2 ,  Ying Liu  2 ,  Yuanyuan Gao  1 ,  Zemin Hou  1 ,  Qian Zhuang  1 ,  Dongyin He  1 ,  Xuebin Zhang  1 ,  Qilong Tan  1 ,  Xuyou Zhu  3 ,  Yingyi Qin  4 ,  Xi Chen  2 ,  Chengdang Xu  2 ,  Cuidong Bian  2 ,  Xinan Wang  2 ,  Chenyang Wang  2 ,  Denglong Wu  2 ,  Shengsong Huang  5 ,  Zhenfei Li  6
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. Department of Pathology, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China.
  • 4. Department of Health Statistics, Second Military Medical University, No. 800 Xiangyin Road, Shanghai 200433, China.
  • 5. Department of Urology, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China. Electronic address: [email protected].
  • 6. 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; Department of Urology, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China. Electronic address: [email protected].
PMID: 35584629 DOI: 10.1016/j.xcrm.2022.100608
Abstract

Novel strategies for prostate Cancer therapy are required to overcome resistance to abiraterone and enzalutamide. Here, we show that increasing 3βHSD1 after abiraterone and enzalutamide treatment is essential for drug resistance, and biochanin A (BCA), as an inhibitor of 3βHSD1, overcomes drug resistance. 3βHSD1 activity increases in cell lines, biopsy samples, and patients after long-term treatment with enzalutamide or abiraterone. Enhanced steroidogenesis, mediated by 3βHSD1, is sufficient to impair enzalutamide function. In patients, accelerated abiraterone metabolism results in a decline of plasma abiraterone as disease progresses. BCA inhibits 3βHSD1 and suppresses prostate Cancer development alone or together with abiraterone and enzalutamide. Daidzein, a BCA analog of dietary origin, is associated with higher plasma abiraterone concentrations and prevented prostate-specific antigen (PSA) increases in abiraterone-resistant patients. Overall, our results show that 3βHSD1 is a promising target to overcome drug resistance, and BCA suppresses disease progression as a 3βHSD1 inhibitor even after abiraterone and enzalutamide resistance.

Keywords
3βHSD1; abiraterone metabolism; androgen; biochanin A; daidzein; enzalutamide resistance; prostate cancer; steroidogenesis.
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