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: | Leung, Professor Hing and Salji, Dr Mark and Sumpton, Mr David and Nixon, Mr Colin and Lilla, Dr Sergio and Ntala, Dr Chara and Clark, Mr William and Zanivan, Professor Sara and Mackay, Dr Gillian and Rushworth, Dr Linda 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 > School 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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