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Schlafen family member 5 (SLFN5) regulates LAT1-mediated mTOR activation in castration-resistant prostate cancer (PART 1)

ABSTRACT: Androgen-deprivation therapy (ADT) is the standard of care for the 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 perform a comparative proteomic analysis of three in vivo, androgen receptor (AR)–driven, orthograft models of CRPC. Differential proteomic analysis reveals that distinct molecular mechanisms, including amino acid (AA) and fatty acid (FA) metabolism, are involved in the response to ADT between the different models. Despite this heterogeneity, we identify SLFN5 as an AR-regulated biomarker in CRPC. SLFN5 expression is high in CRPC tumours and correlates with poor patient outcome. In vivo, SLFN5 depletion strongly impairs tumour growth in castrated condition. Mechanistically, SLFN5 interacts with ATF4 and regulates the expression of LAT1, an essential AA transporter. Consequently, SLFN5 depletion in CRPC cells decreases intracellular levels of essential AA and impairs mTORC1 signalling in a LAT1-dependent manner.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Prostate Adenocarcinoma Cell Line, Epithelial Cell Of Prostate

DISEASE(S): Prostate Carcinoma

SUBMITTER: Sergio Lilla

LAB HEAD: Sara Rossana Zanivan

PROVIDER: PXD021428 | Pride | 2022-04-06

REPOSITORIES: Pride

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			Action	DRS
	041215_SEL_OT_MAS_R08_271115_LNCAP_r02_red_f001.zip	Other
	041215_SEL_OT_MAS_R08_271115_LNCAP_r02_red_f002.zip	Other
	041215_SEL_OT_MAS_R08_271115_LNCAP_r02_red_f003.zip	Other
	041215_SEL_OT_MAS_R08_271115_LNCAP_r02_red_f004.zip	Other
	041215_SEL_OT_MAS_R08_271115_LNCAP_r02_red_f005.zip	Other

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Schlafen family member 5 (SLFN5) regulates LAT1-mediated mTOR activation in castration-resistant prostate cancer (PART 2)

Project description:Androgen-deprivation therapy (ADT) is the standard of care for the 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 perform a comparative proteomic analysis of three in vivo, androgen receptor (AR)–driven, orthograft models of CRPC. Differential proteomic analysis reveals that distinct molecular mechanisms, including amino acid (AA) and fatty acid (FA) metabolism, are involved in the response to ADT between the different models. Despite this heterogeneity, we identify SLFN5 as an AR-regulated biomarker in CRPC. SLFN5 expression is high in CRPC tumours and correlates with poor patient outcome. In vivo, SLFN5 depletion strongly impairs tumour growth in castrated condition. Mechanistically, SLFN5 interacts with ATF4 and regulates the expression of LAT1, an essential AA transporter. Consequently, SLFN5 depletion in CRPC cells decreases intracellular levels of essential AA and impairs mTORC1 signalling in a LAT1-dependent manner.

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The natural compound atraric acid suppresses androgen-regulated neo-angiogenesis of castration‑resistant prostate cancer through angiopoietin 2

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Project description:Background: Patients with locally advanced or recurrent prostate cancer typically undergo androgen deprivation therapy (ADT), but the benefits are often short-lived, and responses are variable. ADT failure results in castration-resistant prostate cancer (CRPC), that inevitably leads to metastasis. We hypothesized that differences in tumor transcriptional programs may reflect differential responses to ADT and subsequent metastasis. Results: We performed whole transcriptome analysis of 20 patient-matched Pre-ADT biopsies and 20 Post-ADT prostatectomy specimens, and identified two subgroups of patients (high impact and low impact groups) that exhibited distinct transcriptional changes in response to ADT. We found that all patients lost AR-dependent subtype (PCS2) transcriptional signatures. The high impact group maintained the more aggressive subtype (PCS1) signal, while the low impact group more resembled an AR-suppressed (PCS3) subtype. Computational analyses identified transcription factor coordinated groups (TFCGs) enriched in the high impact group network. Leveraging a large public dataset of over 800 metastatic and primary samples, we identified 33 TFCGs in common between high impact group and metastatic lesions, including SOX4/FOXA2/GATA4, ERF/ETV5/ETV3/ELF4, and a TFCG containing JUN, JUNB, JUND, FOS, FOSB, and FOSL1. The majority of metastatic TFCGs were subsets of larger TFCGs in the high impact group network, suggesting refinement of critical TFCGs in prostate cancer progression. Conclusions: We have identified TFCGs associated with pronounced initial transcriptional response to ADT, aggressive signatures, and metastasis. Our findings suggest multiple new hypotheses that could lead to novel combination therapies to prevent development of CRPC following ADT.

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