Dataset Information

Subtype and Site Specific-Induced Metabolic Vulnerabilities in Prostate Cancer.

ABSTRACT: Aberrant metabolic functions play a crucial role in prostate cancer progression and lethality. Currently, limited knowledge is available on subtype-specific metabolic features and their implications for treatment. We therefore investigated the metabolic determinants of the two major subtypes of castration-resistant prostate cancer [androgen receptor-expressing prostate cancer (ARPC) and aggressive variant prostate cancer (AVPC)]. Transcriptomic analyses revealed enrichment of gene sets involved in oxidative phosphorylation (OXPHOS) in ARPC tumor samples compared with AVPC. Unbiased screening of metabolic signaling pathways in patient-derived xenograft models by proteomic analyses further supported an enrichment of OXPHOS in ARPC compared with AVPC, and a skewing toward glycolysis by AVPC. In vitro, ARPC C4-2B cells depended on aerobic respiration, while AVPC PC3 cells relied more heavily on glycolysis, as further confirmed by pharmacologic interference using IACS-10759, a clinical-grade inhibitor of OXPHOS. In vivo studies confirmed IACS-10759's inhibitory effects in subcutaneous and bone-localized C4-2B tumors, and no effect in subcutaneous PC3 tumors. Unexpectedly, IACS-10759 inhibited PC3 tumor growth in bone, indicating microenvironment-induced metabolic reprogramming. These results suggest that castration-resistant ARPC and AVPC exhibit different metabolic dependencies, which can further undergo metabolic reprogramming in bone.

Implications

These vulnerabilities may be exploited with mechanistically novel treatments, such as those targeting OXPHOS alone or possibly in combination with existing therapies. In addition, our findings underscore the impact of the tumor microenvironment in reprogramming prostate cancer metabolism.

SUBMITTER: Mossa F

PROVIDER: S-EPMC9812897 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Publications

Subtype and Site Specific-Induced Metabolic Vulnerabilities in Prostate Cancer.

Mossa Federica F Robesti Daniele D Sumankalai Ramachandran R Corey Eva E Titus Mark M Kang Yuqi Y Zhang Jianhua J Briganti Alberto A Montorsi Francesco F Vellano Christopher P CP Marszalek Joseph R JR Frigo Daniel E DE Logothetis Christopher J CJ Gujral Taranjit S TS Dondossola Eleonora E

Molecular cancer research : MCR 20230101 1

Aberrant metabolic functions play a crucial role in prostate cancer progression and lethality. Currently, limited knowledge is available on subtype-specific metabolic features and their implications for treatment. We therefore investigated the metabolic determinants of the two major subtypes of castration-resistant prostate cancer [androgen receptor-expressing prostate cancer (ARPC) and aggressive variant prostate cancer (AVPC)]. Transcriptomic analyses revealed enrichment of gene sets involved ...[more]

PMID: 36112348

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Dataset Information

Subtype and Site Specific-Induced Metabolic Vulnerabilities in Prostate Cancer.

Implications

Publications

Subtype and Site Specific-Induced Metabolic Vulnerabilities in Prostate Cancer.

Similar Datasets

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