TY - JOUR
T1 - CHRM4/AKT/MYCN upregulates interferon alpha-17 in the tumor microenvironment to promote neuroendocrine differentiation of prostate cancer
AU - Wen, Yu-Ching
AU - Tram, Van Thi Ngoc
AU - Chen, Wei-Hao
AU - Li, Chien-Hsiu
AU - Yeh, Hsiu Lien
AU - Thuy Dung, Phan Vu
AU - Jiang, Kuo-Ching
AU - Li, Han-Ru
AU - Huang, Jiaoti
AU - Hsiao, Michael
AU - Chen, Wei-Yu
AU - Liu, Yen-Nien
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/5/4
Y1 - 2023/5/4
N2 - 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.
AB - 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.
KW - Male
KW - Humans
KW - Prostatic Neoplasms/drug therapy
KW - N-Myc Proto-Oncogene Protein/metabolism
KW - Proto-Oncogene Proteins c-akt
KW - Androgen Antagonists/therapeutic use
KW - Interferon-alpha/therapeutic use
KW - Tumor Microenvironment
KW - Cell Line, Tumor
KW - Cell Differentiation
KW - Receptors, Androgen/metabolism
KW - Receptor, Muscarinic M4/therapeutic use
UR - http://www.scopus.com/inward/record.url?scp=85158875796&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85158875796&partnerID=8YFLogxK
U2 - 10.1038/s41419-023-05836-7
DO - 10.1038/s41419-023-05836-7
M3 - Article
C2 - 37142586
SN - 2041-4889
VL - 14
SP - 304
JO - Cell death & disease
JF - Cell death & disease
IS - 5
M1 - 304
ER -
