Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Martinez, RS; Salji, MJ; Rushworth, L; Ntala, C; Rodriguez, Blanco, G; Hedley, A; Clark, W; Peixoto, P; Hervouet, E; Renaude, E; Kung, SHY; Galbraith, LCA; Nixon, C; Lilla, S; MacKay, GM; Fazli, L; Gaughan, L; Sumpton, D; Gleave, ME; Zanivan, S; Blomme, A; Leung, HY.
SLFN5 Regulates LAT1-Mediated mTOR Activation in Castration-Resistant Prostate Cancer.
Cancer Res. 2021; 81(13):3664-3678
Doi: 10.1158/0008-5472.CAN-20-3694
Web of Science
PubMed
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- Co-Autor*innen der Med Uni Graz
- Rodriguez Blanco Giovanny
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- Abstract:
- 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.
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- Activating Transcription Factor 4 - genetics, metabolism
- Animals - administration & dosage
- Apoptosis - administration & dosage
- Biomarkers, Tumor - genetics, metabolism
- Cell Cycle Proteins - genetics, metabolism
- Cell Proliferation - administration & dosage
- Gene Expression Regulation, Neoplastic - administration & dosage
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- Large Neutral Amino Acid-Transporter 1 - genetics, metabolism
- Male - administration & dosage
- Mechanistic Target of Rapamycin Complex 1 - genetics, metabolism
- Metabolome - administration & dosage
- Mice - administration & dosage
- Mice, Nude - administration & dosage
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- Proteome - administration & dosage
- Survival Rate - administration & dosage
- TOR Serine-Threonine Kinases - genetics, metabolism
- Transcriptome - administration & dosage
- Tumor Cells, Cultured - administration & dosage
- Xenograft Model Antitumor Assays - administration & dosage