SLFN5 Regulates LAT1-Mediated mTOR Activation in Castration-Resistant Prostate Cancer
| العنوان: | SLFN5 Regulates LAT1-Mediated mTOR Activation in Castration-Resistant Prostate Cancer |
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| المؤلفون: | Sara Zanivan, Rafael S. Martinez, William C. Clark, Paul Peixoto, Sergio Lilla, Colin Nixon, Laura C. A. Galbraith, Eric Hervouet, Ladan Fazli, Ann Hedley, Sonia H.Y. Kung, Luke Gaughan, Linda K. Rushworth, Hing Y. Leung, Martin E. Gleave, Gillian M. Mackay, Chara Ntala, Mark Salji, David Sumpton, Arnaud Blomme, Giovanny Rodriguez Blanco, Elodie Renaude |
| المصدر: | Cancer Research. 81:3664-3678 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Cancer Research, Proteome, Mice, Nude, Apoptosis, Cell Cycle Proteins, mTORC1, Mechanistic Target of Rapamycin Complex 1, urologic and male genital diseases, Large Neutral Amino Acid-Transporter 1, Mice, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, In vivo, Biomarkers, Tumor, Tumor Cells, Cultured, Animals, Humans, Medicine, PI3K/AKT/mTOR pathway, Cell Proliferation, business.industry, TOR Serine-Threonine Kinases, ATF4, Transporter, Prognosis, medicine.disease, Activating Transcription Factor 4, Xenograft Model Antitumor Assays, Gene Expression Regulation, Neoplastic, Survival Rate, Androgen receptor, Prostatic Neoplasms, Castration-Resistant, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Metabolome, Cancer research, Transcriptome, business, Intracellular |
| الوصف: | Androgen deprivation therapy (ADT) is the standard of care for treatment of nonresectable prostate cancer. Despite high treatment efficiency, most patients ultimately develop lethal castration-resistant prostate cancer (CRPC). In this study, we performed a comparative proteomic analysis of three in vivo, androgen receptor (AR)-responsive orthograft models of matched hormone-naïve prostate cancer and CRPC. Differential proteomic analysis revealed that distinct molecular mechanisms, including amino acid (AA) and fatty acid metabolism, are involved in the response to ADT in the different models. Despite this heterogeneity, Schlafen family member 5 (SLFN5) was identified as an AR-regulated protein in CRPC. SLFN5 expression was high in CRPC tumors and correlated with poor patient outcome. In vivo, SLFN5 depletion strongly impaired tumor growth in castrated conditions. Mechanistically, SLFN5 interacted with ATF4 and regulated the expression of LAT1, an essential AA transporter. Consequently, SLFN5 depletion in CRPC cells decreased intracellular levels of essential AA and impaired mTORC1 signaling in a LAT1-dependent manner. These results confirm that these orthograft models recapitulate the high degree of heterogeneity observed in patients with CRPC and further highlight SLFN5 as a clinically relevant target for CRPC. Significance: This study identifies SLFN5 as a novel regulator of the LAT1 amino acid transporter and an essential contributor to mTORC1 activity in castration-resistant prostate cancer. |
| وصف الملف: | application/pdf |
| تدمد: | 1538-7445 0008-5472 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::349939edf7b5e75f161508418fa75fa8 https://doi.org/10.1158/0008-5472.can-20-3694 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....349939edf7b5e75f161508418fa75fa8 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15387445 00085472 |
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