2. Academic Validation
  3. Acetate utilization promotes hormone therapy resistance in prostate cancer through neuroendocrine differentiation

Acetate utilization promotes hormone therapy resistance in prostate cancer through neuroendocrine differentiation

  • Drug Resist Updat. 2024 Nov:77:101158. doi: 10.1016/j.drup.2024.101158.
Dajun Gao 1,  Yanting Shen 2,  Lingfan Xu 3,  Yi Sun 4,  Hailiang Hu 5,  Bin Xu 6,  Zhong Wang 7,  Huan Xu 8
Affiliations

Affiliations

  • 1 Department of Urology, Shanghai Ninth People's Hospital, Shanghai, China.
  • 2 Department of Urology, Pudong New District Gongli Hospital, Shanghai, China.
  • 3 The First Affiliated Hospital of Anhui Medical University, Anhui, China.
  • 4 Department of Urology, Minimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical University, and Guangdong Key Laboratory of Urology, Guangzhou, China.
  • 5 Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen, China.
  • 6 Department of Urology, Shanghai Ninth People's Hospital, Shanghai, China. Electronic address: 116201@sh9hospital.org.cn.
  • 7 Department of Urology, Shanghai Ninth People's Hospital, Shanghai, China; Department of Urology, Pudong New District Gongli Hospital, Shanghai, China. Electronic address: zhongwang2000@sina.com.
  • 8 Department of Urology, Shanghai Ninth People's Hospital, Shanghai, China. Electronic address: xuhuaneric@hotmail.com.
PMID: 39395327 DOI: 10.1016/j.drup.2024.101158
Abstract

Aims: Tumor fatty acid (FA) metabolic plasticity plays a pivotal role in resistance to therapy and poses limitations to Anticancer strategies. In this study, our aim is to uncover the role of acetate metabolism in neurodifferentiation (NED)-mediated castration-resistant prostate Cancer (CRPC).

Methods: We conducted analyses using LC-MS/MS on clinical prostate Cancer tissue before and after hormone therapy. We established tumor xenograft mouse models, primary tumor cells, and human-derived organoids to detect the novel mechanism of NED and to identify potential therapies.

Results: The hormone therapy-induced upregulation of acetate metabolism was mediated by acyl-CoA synthetase short-chain family member 2 (ACSS2), which increased c-Myc expression for NED induction. Notably, combined treatment with an ACSS2 inhibitor and enzalutamide significantly reduced the xenograft tumor volume.

Conclusion: Our findings uncovered the critical role of acetate metabolism in NED-mediated CRPC and suggest that ACSS2 inhibitors may represent a novel, low-toxicity strategy when combined with hormone therapy for treating patients with NED-mediated CRPC.

Keywords

Acetate; Acyl-CoA synthetase short-chain family member 2 (ACSS2); Castration-resistant prostate cancer (CRPC); Neuroendocrine prostate cancer (NEPC); Short-chain fatty acids (SCFAs).

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