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

Martinez, R. S. et al. (2021) SLFN5 regulates LAT1-mediated mTOR activation in castration-resistant prostate cancer. Cancer Research, 81(13), pp. 3664-3678. (doi: 10.1158/0008-5472.CAN-20-3694) (PMID:33985973)

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Abstract

Androgen-deprivation therapy (ADT) is the standard of care for treatment of non-resectable prostate cancer (PCa). 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 PCa and CRPC. Differential proteomic analysis revealed that distinct molecular mechanisms, including amino acid (AA) and fatty acid (FA) 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 signalling in a LAT1-dependent manner. These results confirm that these orthograft models recapitulate the high degree of heterogeneity observed in CRPC patients and further highlight SLFN5 as a clinically relevant target for CRPC.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Nixon, Mr Colin and Lilla, Dr Sergio and Clark, Mr William and Leung, Professor Hing and Zanivan, Professor Sara and Rushworth, Dr Linda and Salji, Dr Mark and Sumpton, Mr David and Ntala, Dr Chara and Mackay, Dr Gillian and Galbraith, Dr Laura
Creator Roles:
Salji, M. J.Conceptualization, Resources, Formal analysis, Validation, Investigation, Writing – review and editing
Rushworth, L.Investigation, Methodology, Project administration, Writing – review and editing
Ntala, C.Data curation, Formal analysis
Clark, W.Resources, Methodology
Galbraith, L. C.A.Methodology
Nixon, C.Methodology
Lilla, S.Resources, Software, Formal analysis, Methodology
Mackay, G. M.Methodology
Sumpton, D.Resources, Software, Formal analysis, Methodology
Zanivan, S.Formal analysis, Supervision, Funding acquisition, Methodology, Writing – review and editing
Leung, H.Conceptualization, Resources, Supervision, Funding acquisition, Investigation, Project administration, Writing – review and editing
Authors: Martinez, R. S., Salji, M. J., Rushworth, L., Ntala, C., Rodriguez Blanco, G., Hedley, A., Clark, W., Peixoto, P., Hervouet, E., Renaude, E., Kung, S. H. Y., Galbraith, L. C.A., Nixon, C., Lilla, S., Mackay, G. M., Fazli, L., Gaughan, L., Sumpton, D., Gleave, M. E., Zanivan, S., Blomme, A., and Leung, H. Y.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Cancer Research
Publisher:American Association for Cancer Research
ISSN:0008-5472
ISSN (Online):1538-7445
Published Online:13 May 2021
Copyright Holders:Copyright © 2021 American Association for Cancer Research
First Published:First published in Cancer Research 81(13): 3664-3678
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
170128Quantitative proteomic analysis of castrate-resistant prostate cancerHing LeungMedical Research Council (MRC)MR/L017997/1Institute of Cancer Sciences