SLFN5 Regulates LAT1-Mediated mTOR Activation in Castration-Resistant Prostate Cancer.

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.

• Authors: Rafael S Martinez, Mark J Salji, Linda Rushworth, Chara Ntala, Giovanny Rodriguez Blanco, Ann Hedley, William Clark, Paul Peixoto, Eric Hervouet, Elodie Renaude, Sonia H Y Kung, Laura C A Galbraith, Colin Nixon, Sergio Lilla, Gillian M MacKay, Ladan Fazli, Luke Gaughan, David Sumpton, Martin E Gleave, Sara Zanivan, Arnaud Blomme, Hing Y Leung
• Journal: Cancer research (Cancer Res) Vol. 81 Issue 13 Pg. 3664-3678 (07 01 2021) ISSN: 1538-7445 [Electronic] United States
• PMID: 33985973 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• ATF4 protein, human
• Biomarkers, Tumor
• Cell Cycle Proteins
• Large Neutral Amino Acid-Transporter 1
• Proteome
• SLC7A5 protein, human
• SLFN5 protein, human
• Activating Transcription Factor 4
• MTOR protein, human
• Mechanistic Target of Rapamycin Complex 1
• TOR Serine-Threonine Kinases

Topics

• Activating Transcription Factor 4 (genetics, metabolism)
• Animals
• Apoptosis
• Biomarkers, Tumor (genetics, metabolism)
• Cell Cycle Proteins (genetics, metabolism)
• Cell Proliferation
• Gene Expression Regulation, Neoplastic
• Humans
• Large Neutral Amino Acid-Transporter 1 (genetics, metabolism)
• Male
• Mechanistic Target of Rapamycin Complex 1 (genetics, metabolism)
• Metabolome
• Mice
• Mice, Nude
• Prognosis
• Prostatic Neoplasms, Castration-Resistant (genetics, metabolism, pathology)
• Proteome
• Survival Rate
• TOR Serine-Threonine Kinases (genetics, metabolism)
• Transcriptome
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays