MP20-20 CHAPERONE-MEDIATED AUTOPHAGY PROMOTES PCA SURVIVAL DURING ARPI THROUGH SELECTIVE PROTEOME AND PATHWAY REMODELING

Abstract

You have accessJournal of UrologyCME1 Apr 2023MP20-20 CHAPERONE-MEDIATED AUTOPHAGY PROMOTES PCA SURVIVAL DURING ARPI THROUGH SELECTIVE PROTEOME AND PATHWAY REMODELING Nicholas Nikesitch, Eliana Beraldi, Fan Zhang, Hans Adomat, Robert Bell, Kotaro Suzuki, Ladan Fazli, Sonia Kung, Christopher Wells, Nicholas Pinette, Neetu Saxena, Yuzhuo Wang, and Martin Gleave Nicholas NikesitchNicholas Nikesitch More articles by this author , Eliana BeraldiEliana Beraldi More articles by this author , Fan ZhangFan Zhang More articles by this author , Hans AdomatHans Adomat More articles by this author , Robert BellRobert Bell More articles by this author , Kotaro SuzukiKotaro Suzuki More articles by this author , Ladan FazliLadan Fazli More articles by this author , Sonia KungSonia Kung More articles by this author , Christopher WellsChristopher Wells More articles by this author , Nicholas PinetteNicholas Pinette More articles by this author , Neetu SaxenaNeetu Saxena More articles by this author , Yuzhuo WangYuzhuo Wang More articles by this author , and Martin GleaveMartin Gleave More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003245.20AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The androgen receptor (AR) plays an important role in PCa metabolism, with androgen receptor pathway inhibition (ARPI) subjecting PCa cells to acute metabolic stress caused by reduced biosynthesis and energy production. Defining acute stress response mechanisms that alleviate ARPI stress and therefore mediate prostate cancer (PCa) treatment resistance will help improve therapeutic outcomes of patients treated with ARPI. METHODS: CMA induction and activity was studied within several in-vitro, in-vivo and ex-vivo PCa models using QPCR, Western Blot and CMA-reporter assays. CMA upregulation/downregulation on PCa growth was measured in-vitro and in-vivo via cell confluence or tumour volume/PSA levels. Proteome profiling of PCa cells was perfromed by TMT mass spec, with metabolic assays performed using western blot, colormetric and flow cytometry. RESULTS: We identified the up-regulation of chaperone-mediated autophagy (CMA) in response to acute ARPI stress, which persisted in castration-resistant PCa (CRPC); previously undefined in PCa. CMA is a selective protein degradation pathway and a key stress response mechanism up-regulated under several stress stimuli, including metabolic stress. Through selective protein degradation, CMA orchestrates the cellular stress response by regulating cellular pathways through selective proteome remodeling. Through broad-spectrum proteomic analysis, CMA coordinates metabolic reprogramming of PCa cells to sustain PCa growth and survival during ARPI; through the upregulation of mTORC1 signaling and pathways associated with PCa biosynthesis and energetics. This not only promoted PCa growth during ARPI, but also promoted the emergence of CRPC in-vivo. During CMA inhibition, PCa metabolism is compromised, leading to ATP depletion, resulting in a profound anti-proliferative effect on PCa cells, and is enhanced when combined with ARPI. Furthermore, CMA inhibition prevented in-vivo tumour formation, and also re-sensitized enzalutamide-resistant cell lines in-vitro. The profound anti-proliferative effect of CMA inhibition was attributed to cell cycle arrest mediated through p53 transcriptional repression of E2F target genes. CONCLUSIONS: In summary, CMA is an acute ARPI stress response mechanism, essential in alleviating ARPI induced metabolic stress, essential for ensuring PCa growth and survival. CMA plays a critical role in the development of ARPI resistance in PCa. Source of Funding: Terry Fox New Frontiers Program Project (1062) and PCFBC Grant-In-Aid Program © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e283 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Nicholas Nikesitch More articles by this author Eliana Beraldi More articles by this author Fan Zhang More articles by this author Hans Adomat More articles by this author Robert Bell More articles by this author Kotaro Suzuki More articles by this author Ladan Fazli More articles by this author Sonia Kung More articles by this author Christopher Wells More articles by this author Nicholas Pinette More articles by this author Neetu Saxena More articles by this author Yuzhuo Wang More articles by this author Martin Gleave More articles by this author Expand All Advertisement PDF downloadLoading ...