PGC1α Inhibits Polyamine Synthesis to Suppress Prostate Cancer Aggressiveness.

Abstract

Although tumorigenesis is dependent on the reprogramming of cellular metabolism, the metabolic pathways engaged in the formation of metastases remain largely unknown. The transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) plays a pleiotropic role in the control of cancer cell metabolism and has been associated with a good prognosis in prostate cancer. Here, we show that PGC1α represses the metastatic properties of prostate cancer cells via modulation of the polyamine biosynthesis pathway. Mechanistically, PGC1α inhibits the expression of c-MYC and ornithine decarboxylase 1 (ODC1), the rate-limiting enzyme for polyamine synthesis. Analysis of in vivo metastases and clinical data from patients with prostate cancer support the proposition that the PGC1α/c-MYC/ODC1 axis regulates polyamine biosynthesis and prostate cancer aggressiveness. In conclusion, downregulation of PGC1α renders prostate cancer cells dependent on polyamine to promote metastasis. SIGNIFICANCE: These findings show that a major regulator of mitochondrial metabolism controls polyamine synthesis and prostate cancer aggressiveness, with potential applications in therapy and identification of new biomarkers.

• Authors: Lisa Kaminski, Stéphanie Torrino, Maeva Dufies, Zied Djabari, Romain Haider, François-René Roustan, Emilie Jaune, Kathiane Laurent, Nicolas Nottet, Jean-François Michiels, Maeva Gesson, Stéphane Rocchi, Nathalie M Mazure, Matthieu Durand, Jean-François Tanti, Damien Ambrosetti, Stephan Clavel, Issam Ben-Sahra, Frédéric Bost
• Journal: Cancer research (Cancer Res) Vol. 79 Issue 13 Pg. 3268-3280 (07 01 2019) ISSN: 1538-7445 [Electronic] United States
• PMID: 31064849 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Biomarkers, Tumor
• Dicarboxylic Acid Transporters
• MYC protein, human
• Mitochondrial Membrane Transport Proteins
• PPARGC1A protein, human
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Polyamines
• Proto-Oncogene Proteins c-myc
• SLC25A21 protein, human

Topics

• Aged
• Aged, 80 and over
• Animals
• Apoptosis
• Biomarkers, Tumor (genetics, metabolism)
• Cell Proliferation
• Dicarboxylic Acid Transporters (genetics, metabolism)
• Follow-Up Studies
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Mice
• Mice, Nude
• Middle Aged
• Mitochondria (metabolism, pathology)
• Mitochondrial Membrane Transport Proteins (genetics, metabolism)
• Neoplasm Metastasis
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha (genetics, metabolism)
• Polyamines (metabolism)
• Prognosis
• Prostatic Neoplasms (genetics, metabolism, pathology)
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• Signal Transduction
• Survival Rate
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays