2. Academic Validation
  3. CHRM4/AKT/MYCN upregulates interferon alpha-17 in the tumor microenvironment to promote neuroendocrine differentiation of prostate cancer

CHRM4/AKT/MYCN upregulates interferon alpha-17 in the tumor microenvironment to promote neuroendocrine differentiation of prostate cancer

  • Cell Death Dis. 2023 May 4;14(5):304. doi: 10.1038/s41419-023-05836-7.
Yu-Ching Wen 1 2 3,  Van Thi Ngoc Tram 4,  Wei-Hao Chen 5,  Chien-Hsiu Li 6,  Hsiu-Lien Yeh 5,  Phan Vu Thuy Dung 5,  Kuo-Ching Jiang 5,  Han-Ru Li 5,  Jiaoti Huang 7,  Michael Hsiao 6,  Wei-Yu Chen 8 9,  Yen-Nien Liu 10 11
Affiliations

Affiliations

  • 1 Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei, 11696, Taiwan.
  • 2 Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
  • 3 TMU Research Center of Urology and Kidney, Taipei Medical University, Taipei, 11031, Taiwan.
  • 4 International PhD Program in Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
  • 5 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan.
  • 6 Genomics Research Center, Academia Sinica, Taipei, 11529, Taiwan.
  • 7 Department of Pathology, Duke University Medical Center, Durham, NC, 27710, USA.
  • 8 Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, 11696, Taiwan. 1047@tmu.edu.tw.
  • 9 Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan. 1047@tmu.edu.tw.
  • 10 International PhD Program in Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan. liuy@tmu.edu.tw.
  • 11 TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, 11031, Taiwan. liuy@tmu.edu.tw.
PMID: 37142586 DOI: 10.1038/s41419-023-05836-7
Abstract

Current treatment options for prostate Cancer focus on targeting Androgen Receptor (AR) signaling. Inhibiting effects of AR may activate neuroendocrine differentiation and lineage plasticity pathways, thereby promoting the development of neuroendocrine prostate Cancer (NEPC). Understanding the regulatory mechanisms of AR has important clinical implications for this most aggressive type of prostate Cancer. Here, we demonstrated the tumor-suppressive role of the AR and found that activated AR could directly bind to the regulatory sequence of Muscarinic Acetylcholine Receptor 4 (CHRM4) and downregulate its expression. CHRM4 was highly expressed in prostate Cancer cells after androgen-deprivation therapy (ADT). CHRM4 overexpression may drive neuroendocrine differentiation of prostate Cancer cells and is associated with immunosuppressive cytokine responses in the tumor microenvironment (TME) of prostate Cancer. Mechanistically, CHRM4-driven Akt/MYCN signaling upregulated the interferon alpha 17 (IFNA17) cytokine in the prostate Cancer TME after ADT. IFNA17 mediates a feedback mechanism in the TME by activating the CHRM4/Akt/MYCN signaling-driven immune checkpoint pathway and neuroendocrine differentiation of prostate Cancer cells. We explored the therapeutic efficacy of targeting CHRM4 as a potential treatment for NEPC and evaluated IFNA17 secretion in the TME as a possible predictive prognostic biomarker for NEPC.

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