{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T15:05:38Z","timestamp":1787843138859,"version":"build-2784847793"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T00:00:00Z","timestamp":1752710400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>The development of prostate cancer (PCa) remains a major health threat for men worldwide. Calcium\/Calmodulin signaling pathway has been implicated to the initiation and progression of diverse human cancers. Loss or downregulation of Purkinje cell protein 4 (PCP4), is frequently observed in some prostate cancer patients, particularly those with castration-resistant prostate cancer (CRPC).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Public datasets were used to analyze PCP4 expression and the relationship between PCP4 expression and clinicopathological characteristics of PCa patients. Gain- and loss-of-function studies in PCa cell lines and mouse models were performed to characterize the role of PCP4 in tumor progression. A series of molecular and biochemical experiments were carried out in PCa cell lines to investigate the mechanism underlying PCP4-mediated tumor suppression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>(1) <jats:italic>PCP4<\/jats:italic> gene loss occurs at high frequency in PCa patients, and decreased expression of PCP4 correlates with poor prognosis of PCa, particularly CRPC development; (2) <jats:italic>TMPRSS2-ERG<\/jats:italic> fusion frequently co-occurs with <jats:italic>PCP<\/jats:italic>4 deletion; (3) PCP4 suppresses prostate cancer progression <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>; (4) PCP4 is an androgen receptor (AR) suppressed gene; (5) PCP4 was involved in the stabilization of CAMKK2 protein; (6) PCP4 inhibits PCa progression by regulating Ca<jats:sup>2+<\/jats:sup>\/CAMKK2\/AMPK\/AR signaling axis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings elucidate the molecular mechanism that PCP4 downregulation promotes PCa progression via Ca<jats:sup>2+<\/jats:sup>\/CAMKK2\/AMPK\/AR pathway, highlighting its significance in CRPC development.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1616046","type":"journal-article","created":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T07:05:16Z","timestamp":1752735916000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["PCP4 inhibits the progression of prostate cancer through Ca2+\/CAMKK2\/AMPK\/AR 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