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SLFN5 regulates LAT1-Mediated mTOR activation in castration-resistant prostate cancer

Lookup NU author(s): Dr Luke GaughanORCiD

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This is the authors' accepted manuscript of an article that has been published in its final definitive form by American Association for Cancer Research Inc., 2021.

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Abstract

© 2021 American Association for Cancer Research.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-naive 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.

Publication metadata

Author(s): Martinez RS, Salji MJ, Rushworth L, Ntala C, Blanco GR, 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

Publication type: Article

Publication status: Published

Journal: Cancer Research

Year: 2021

Volume: 81

Issue: 13

Pages: 3664-3678

Print publication date: 01/07/2021

Online publication date: 13/05/2021

Acceptance date: 11/05/2021

Date deposited: 10/09/2025

ISSN (print): 0008-5472

ISSN (electronic): 1538-7445

Publisher: American Association for Cancer Research Inc.

URL: https://doi.org/10.1158/0008-5472.CAN-20-3694

DOI: 10.1158/0008-5472.CAN-20-3694

PubMed id: 33985973

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