Multiple metabolic pathways fuel the truncated tricarboxylic acid cycle of the prostate to sustain constant citrate production and secretion

Molecular Metabolism

Yves Fradet¹  Chantal Atallah¹  Line Berthiaume¹  Dominic Bastien¹  Bertrand Neveu¹  Kevin Gonthier¹  Aurélie Lacouture²  Mario Harvey²  Isabelle Laverdière²  Étienne Audet-Walsh³  Frédéric Pouliot⁴  Jean-François Pelletier⁵  Cindy Weidmann⁵  Cynthia Jobin⁵  Louis Lacombe⁵  Lilianne Frégeau-Proulx⁵  Alain Bergeron⁵ 

[1] Centre de Recherche sur le Cancer de l'Université Laval, Québec, QC, Canada;Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec, QC, Canada;Oncology Research Axis, CHU de Québec – Université Laval Research Center, Québec, QC, Canada;Centre de Recherche sur le Cancer de l'Université Laval, Québec, QC, Canada;Endocrinology – Nephrology Research Axis, CHU de Québec – Université Laval Research Center, Québec, QC, Canada;

关键词: Prostate cancer;    Organoids;    TCA cycle;    Androgen;    Fertility;   

DOI  :  

来源: DOAJ

【 摘 要 】

Objective: The prostate is metabolically unique: it produces high levels of citrate for secretion via a truncated tricarboxylic acid (TCA) cycle to maintain male fertility. In prostate cancer (PCa), this phenotype is reprogrammed, making it an interesting therapeutic target. However, how the truncated prostate TCA cycle works is still not completely understood. Methods: We optimized targeted metabolomics in mouse and human organoid models in ex vivo primary culture. We then used stable isotope tracer analyses to identify the pathways that fuel citrate synthesis. Results: First, mouse and human organoids were shown to recapitulate the unique citrate-secretory program of the prostate, thus representing a novel model that reproduces this unusual metabolic profile. Using stable isotope tracer analysis, several key nutrients were shown to allow the completion of the prostate TCA cycle, revealing a much more complex metabolic profile than originally anticipated. Indeed, along with the known pathway of aspartate replenishing oxaloacetate, glutamine was shown to fuel citrate synthesis through both glutaminolysis and reductive carboxylation in a GLS1-dependent manner. In human organoids, aspartate entered the TCA cycle at the malate entry point, upstream of oxaloacetate. Our results demonstrate that the citrate-secretory phenotype of prostate organoids is supported by the known aspartate–oxaloacetate–citrate pathway, but also by at least three additional pathways: glutaminolysis, reductive carboxylation, and aspartate–malate conversion. Conclusions: Our results add a significant new dimension to the prostate citrate-secretory phenotype, with at least four distinct pathways being involved in citrate synthesis. Better understanding this distinctive citrate metabolic program will have applications in both male fertility as well as in the development of novel targeted anti-metabolic therapies for PCa.

【 授权许可】

Unknown