Androgen receptor inhibition induces metabolic reprogramming and increased reliance on oxidative mitochondrial metabolism in prostate cancer

Crowell, Preston D.; Giafaglione, Jenna M.; Jones, Anthony E.; Nunley, Nicholas M.; Hashimoto, Takahiro; Delcourt, Amelie M.L.; Petcherski, Anton; Bernard, Matthew J.; Huang, Rong; Low, Jin-Yih; Matulionis, Nedas; Guan, Xiangnan; Navone, Nora M.; Alumkal, Joshi J.; Haffner, Michael C.; Ye, Huihui; Zoubeidi, Amina; Christofk, Heather R.; Divakaruni, Ajit S.; Goldstein, Andrew S.

doi:10.1101/2022.05.31.494200

Cited by 2 publications

(1 citation statement)

References 56 publications

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“…Other groups have reported the AR-dependent transcriptional upregulation of many components of the glycolytic pathway, including the enzyme lactate dehydrogenase A (LDHA) responsible for the conversion of pyruvate to lactate. Hyperpolarized (HP) magnetic resonance spectroscopic imaging (MRSI) confirmed an increased conversion of [1- 13 C] pyruvate to lactate in patient-derived xenografts (PDX) from AR-driven compared to AR-negative CRPC, suggesting AR-mediated modulation of aerobic glycolysis [ 30 , 31 , 32 , 33 ]. Thus, both AR-independent and -dependent mechanisms may contribute to increased aerobic glycolysis in advanced PCa.…”

Section: Introductionmentioning

confidence: 99%

Lactate as Key Metabolite in Prostate Cancer Progression: What Are the Clinical Implications?

Chetta

Sriram

Zadra

2023

Cancers

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Advanced prostate cancer represents the fifth leading cause of cancer death in men worldwide. Although androgen-receptor signaling is the major driver of the disease, evidence is accumulating that disease progression is supported by substantial metabolic changes. Alterations in de novo lipogenesis and fatty acid catabolism are consistently reported during prostate cancer development and progression in association with androgen-receptor signaling. Therefore, the term “lipogenic phenotype” is frequently used to describe the complex metabolic rewiring that occurs in prostate cancer. However, a new scenario has emerged in which lactate may play a major role. Alterations in oncogenes/tumor suppressors, androgen signaling, hypoxic conditions, and cells in the tumor microenvironment can promote aerobic glycolysis in prostate cancer cells and the release of lactate in the tumor microenvironment, favoring immune evasion and metastasis. As prostate cancer is composed of metabolically heterogenous cells, glycolytic prostate cancer cells or cancer-associated fibroblasts can also secrete lactate and create “symbiotic” interactions with oxidative prostate cancer cells via lactate shuttling to sustain disease progression. Here, we discuss the multifaceted role of lactate in prostate cancer progression, taking into account the influence of the systemic metabolic and gut microbiota. We call special attention to the clinical opportunities of imaging lactate accumulation for patient stratification and targeting lactate metabolism.

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Section: Introductionmentioning

confidence: 99%

Lactate as Key Metabolite in Prostate Cancer Progression: What Are the Clinical Implications?

Chetta

Sriram

Zadra

2023

Cancers

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Subtype and Site Specific–Induced Metabolic Vulnerabilities in Prostate Cancer

Mossa

Robesti

Ramachandran

et al. 2022

Molecular Cancer Research

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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.

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Androgen receptor inhibition induces metabolic reprogramming and increased reliance on oxidative mitochondrial metabolism in prostate cancer

Cited by 2 publications

References 56 publications

Lactate as Key Metabolite in Prostate Cancer Progression: What Are the Clinical Implications?

Lactate as Key Metabolite in Prostate Cancer Progression: What Are the Clinical Implications?

Subtype and Site Specific–Induced Metabolic Vulnerabilities in Prostate Cancer

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