Pd09-12 Unlocking the Potential of Spermine: Targeting Hmox1-Induced Mitophagy in Prostate Cancer Therapy

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology II (PD09)1 May 2024PD09-12 UNLOCKING THE POTENTIAL OF SPERMINE: TARGETING HMOX1-INDUCED MITOPHAGY IN PROSTATE CANCER THERAPY Jingkai Sun, Peter Ka-Fung Chiu, Tingting Xie, Jeremy Yuen-Chun Teoh, Vincy Wing-Sze Ho, Peng Huang, and Chi-Fai Ng Jingkai SunJingkai Sun , Peter Ka-Fung ChiuPeter Ka-Fung Chiu , Tingting XieTingting Xie , Jeremy Yuen-Chun TeohJeremy Yuen-Chun Teoh , Vincy Wing-Sze HoVincy Wing-Sze Ho , Peng HuangPeng Huang , and Chi-Fai NgChi-Fai Ng View All Author Informationhttps://doi.org/10.1097/01.JU.0001008572.33286.63.12AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Spermine (SPM) is a metabolite with significantly reduced levels in PCa. Decreased SPM levels may affect the physiological function and environment of normal prostate cells, which might even lead to or sustain oncogenic signalling pathways. However, the role of SPM in promoting PCa progression remains poorly understood. This study aimed to reveal the role of SPM in PCa and to investigate the relationship between SPM and heme oxygenase 1 (HMOX1), which has recently been proven to be involved in the mitochondrial biogenesis and regarded as a mitochondrial quality control protein. METHODS: SPM was detected in PCa urines, tissue, and cell lines by LC/MS and IHC. mRNA and ATAC seq integrated analysis in SPM-treated PCa cells was performed to reveal the signaling pathway for SPM mechanism. TCA cycle intermediates and polyamines in the SPM-treated PCa cells were also measured and performed correlation analyses. Flow cytometry, western blot, transmission electron microscopy, and confocal microscopy were performed to determine and analyze mitophagy. Relative gain/loss of function assays for HMOX1 were applied to investigate the biological mechanism of SPM in PCa. ChIP-seq was conducted to evaluate the relationship between SPM-regulated genes and H3K27ac. The anti-proliferation effect of SPM in PCa was also assessed in vivo by bioluminescence on the orthotopic PCa mice model. RESULTS: Decreased SPM level was found in urine and tissue from PCa patients. SPM was found to inhibit the PCa cells' proliferation, migration, and invasion. mRNA sequencing indicated the potential pathway of SPM is mitophagy. The correlated ATAC-seq data showed the sequencing tracks for the HMOX1 locus contain higher ATAC-seq peaks at the promoter under SPM treatment. SPM influenced and modified the epigenetic landscape of PCa cells. Mechanistically, SPM was demonstrated to upregulate HMOX1 by altering chromatin accessibility, amplify PINK1-PARKIN-mediated mitophagy, and induce PCa cell death. SPM disrupted the mitochondrial membrane potential and triggered autophagic flow engulfing the damaged mitochondria. Conversely, the induction of mitochondrial mass control and cell death from SPM could be reversed by silencing the HMOX1 or autophagy inhibitors. In in vivo mice experiments, spermine was injected intratumorally, intraperitoneally, and orally by gavage, and all three modalities demonstrated anti-tumor effects. CONCLUSIONS: Our findings suggest SPM kills PCa cells via overactivation of HMOX1 and induction of mitophagy, which may serve as a promising local or systemic therapy against PCa. Source of Funding: Supported by Hongkong RGC research matching grant 8601454 © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e183 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Jingkai Sun More articles by this author Peter Ka-Fung Chiu More articles by this author Tingting Xie More articles by this author Jeremy Yuen-Chun Teoh More articles by this author Vincy Wing-Sze Ho More articles by this author Peng Huang More articles by this author Chi-Fai Ng More articles by this author Expand All Advertisement PDF downloadLoading ...