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

Yu-Ching Wen, Van Thi Ngoc Tram, Wei-Hao Chen, Chien-Hsiu Li, Hsiu Lien Yeh, Phan Vu Thuy Dung, Kuo-Ching Jiang, Han-Ru Li, Jiaoti Huang, Michael Hsiao, Wei-Yu Chen, Yen-Nien Liu

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)304
JournalCell death & disease
Volume14
Issue number5
DOIs
Publication statusPublished - May 4 2023

Keywords

  • Male
  • Humans
  • Prostatic Neoplasms/drug therapy
  • N-Myc Proto-Oncogene Protein/metabolism
  • Proto-Oncogene Proteins c-akt
  • Androgen Antagonists/therapeutic use
  • Interferon-alpha/therapeutic use
  • Tumor Microenvironment
  • Cell Line, Tumor
  • Cell Differentiation
  • Receptors, Androgen/metabolism
  • Receptor, Muscarinic M4/therapeutic use

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