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

• Published in: Cell death & disease 2023-05, Vol.14 (5), p.304-304, Article 304
• Main Authors: Wen, Yu-Ching, Tram, Van Thi Ngoc, Chen, Wei-Hao, Li, Chien-Hsiu, Yeh, Hsiu-Lien, Thuy Dung, Phan Vu, Jiang, Kuo-Ching, Li, Han-Ru, Huang, Jiaoti, Hsiao, Michael, Chen, Wei-Yu, Liu, Yen-Nien
• Format: Article
• Language: English
• Subjects: 13/1; 13/105; 13/51; 13/95; 38/109; 38/22; 38/44; 38/70; 631/67/327; 692/308/2056; 692/53/2422; 692/699/2768/1753; Acetylcholine receptors (muscarinic); AKT protein; Androgen Antagonists - therapeutic use; Androgen receptors; Androgens; Antibodies; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell Differentiation; Cell Line, Tumor; Cytokines; Humans; Immune checkpoint; Immunology; Interferon; Interferon-alpha - therapeutic use; Life Sciences; Male; N-Myc Proto-Oncogene Protein - metabolism; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Proto-Oncogene Proteins c-akt; Receptor, Muscarinic M4 - therapeutic use; Receptors, Androgen - metabolism; Regulatory sequences; Signal transduction; Tumor Microenvironment; Tumors
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-023-05836-7

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.