1. Academic Validation
  2. AR antagonists develop drug resistance through TOMM20 autophagic degradation-promoted transformation to neuroendocrine prostate cancer

AR antagonists develop drug resistance through TOMM20 autophagic degradation-promoted transformation to neuroendocrine prostate cancer

  • J Exp Clin Cancer Res. 2023 Aug 10;42(1):204. doi: 10.1186/s13046-023-02776-0.
Linglong Yin 1 2 3 Yubing Ye 3 Ling Zou 3 Jinli Lin 3 Yi Dai 3 Yongming Fu 1 2 Youhong Liu 4 5 Yuchong Peng 1 2 Yingxue Gao 4 5 Yuxin Fu 4 5 Xuli Qi 4 5 Tanggang Deng 1 2 Songwei Zhang 4 5 Xiong Li 6 7 8 9
Affiliations

Affiliations

  • 1 Key Laboratory of Clinical Precision Pharmacy of Guangdong Higher Education Institutes, The First Affiliated Hospital, Guangdong Pharmaceutical University, 19 Nonglinxia Road, Yuexiu District, Guangzhou, Guangdong, China.
  • 2 Clinical Pharmacy, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangdong, China.
  • 3 School of Clinical Pharmacy, Guangdong Pharmaceutical University, Guangdong, China.
  • 4 Department of Oncology, Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China.
  • 5 Hunan Key Laboratory of Molecular Radiation Oncology, Xiangya Hospital, Central South University, Changsha, China.
  • 6 Key Laboratory of Clinical Precision Pharmacy of Guangdong Higher Education Institutes, The First Affiliated Hospital, Guangdong Pharmaceutical University, 19 Nonglinxia Road, Yuexiu District, Guangzhou, Guangdong, China. lixiong@gdpu.edu.cn.
  • 7 Clinical Pharmacy, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangdong, China. lixiong@gdpu.edu.cn.
  • 8 School of Clinical Pharmacy, Guangdong Pharmaceutical University, Guangdong, China. lixiong@gdpu.edu.cn.
  • 9 NMPA Key Laboratory for Technology Research and Evaluation of Pharmacovigilance, Guangdong Pharmaceutical University, Guangdong, China. lixiong@gdpu.edu.cn.
Abstract

Background: Prostate Cancer(PCa) is the most commonly occurring male Cancer in the USA. Abiraterone or Enzalutamide have been approved for the treatment of metastatic castration-resistant prostate Cancer (CRPC). However, the treatment-emergent neuroendocrine PCa (t-NEPC) may develop, resulting in drug resistance in about 10-17% CRPC patients. The detailed mechanisms remain unclear..

Methods: The expression correlation of TOMM20 and AR in PCa was determined by analyzing publicly available datasets, or by IHC staining in tumor specimens. The protein interaction of TOMM20 and AR was validated by co-immunoprecipitation or GST pull-down assay. The impact of TOMM20 depletion on drug sensitivity were elucidated by assays of cell proliferation, invasion, sphere formation, xenograft growth and intravenous metastasis. The intracellular ROS level was measured by flow cytometry, and the NEPC transdifferentiation and characteristics of Cancer stem-like cells were validated by RNA-seq, RT-PCR and western blotting.

Results: The protein level of TOMM20 is positively correlated with AR in PCa cells and specimens. TOMM20 protein physically interacts with AR. AR antagonists induced the protein degradation of TOMM20 through autophagy-lysosomal pathway, thereby elevating the intracellular ROS level and activating PI3K/Akt signaling pathway. When TOMM20 was depleted, PCa cells underwent EMT, acquired the characteristics of Cancer stem-like cells, and developed resistance to AR antagonists. The stable depletion of TOMM20 promoted the transdifferentiation of PCa adenocarcinoma into NEPC and metastasis. Conversely, the rescue of TOMM20 re-sensitized the resistant PCa cells to AR antagonists.

Conclusions: TOMM20 protein degradation induced by AR antagonists promoted the transdifferentiation of PCa to NEPC, thereby revealing a novel molecular mechanism by which AR antagonists develop drug resistance through mitochondrial outer membrane-mediated signaling pathway. These findings suggested that the decreasing or loss of TOMM20 expression in PCa tissues might become a useful predictor of PCa resistance to AR antagonists.

Keywords

AR Antagonists; Autophagic Degradation; Drug Resistance; Neuroendocrine Prostate Cancer; TOMM20.

Figures
Products