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

[en] 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.

Disciplines :

Biochemistry, biophysics & molecular biology

Author, co-author :

Martinez, Rafael S.

Salji, Mark J.

Rushworth, Linda

Ntala, Chara

Rodriguez Blanco, Giovanny

Hedley, Ann

Clark, William

Peixoto, Paul

Hervouet, Eric

Renaude, Elodie

More authors (12 more)

^✱ These authors have contributed equally to this work.

Language :

English

Title :

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

Publication date :

2021

Journal title :

Cancer Research

ISSN :

0008-5472

eISSN :

1538-7445

Publisher :

American Association for Cancer Research, United States - Maryland

Peer reviewed :

Peer Reviewed verified by ORBi

Commentary :

Available on ORBi :

since 01 June 2021

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