PGC-1alpha drives an onco-metabolic program to limit prostate cancer aggressiveness L. Kaminski1, R. Haider2, K. Laurent1, D. Ambrosetti3, J.F. Michiels3, M. Durand2, N.M. Mazure1,S. Clavel1, I.Ben-Sahra4, F. Bost1 Prostate cancer (PCa) is the third cause of cancer death in men and deaths are due to advanced metastatic PCa. Metabolic reprogramming has been shown to play a major role in cancer aggressiveness; however, the metabolic pathways implicated in the formation of metastasis are poorly understood. In this context, we chose to study peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1) which plays a major role in cell metabolism and more specifically the regulation of Oxidative Phosphorylation. PGC-1 is a master regulator of mitochondrial biogenesis and a recent paper suggests that low levels of PGC-1 may be associated with a poor prognosis in PCa. Thus, we decided to study the role of PGC-1 on PCa aggressiveness and metabolism. We performed a knockdown (KD) of PGC-1 in prostate cancer cell lines using different shRNA. PGC-1 KD enhanced PCa cell proliferation, migration and invasion of LNCaP and DU145 cells. Conversely, overexpression of PGC-1 decreased cell migration. To determine the molecular mechanism implicated in this phenotype, we analyzed the expression of several genes controlling oncogenesis and metabolism. We showed that genes implicated in glutaminolysis and proto-oncogenes were up regulated in PGC-1 KD cells. To characterize the metabolic modifications modulated by PGC-1, we performed a steady-state metabolomic analysis. We demonstrated that the polyamine pathway (putrescine, spermine) is significantly up-regulated in cells where PGC1- is downregulated. In accordance, the ornithine decarboxylase (ODC), a rate limiting enzyme of this pathway is up-regulated in PGC-1 KD cells. We then decided to inhibit ODC with DFMO (α-difluorométhylornithine) and performed migration assay. We showed that the pro-migratory effects of PGC-1 KD cells are blocked by DFMO. Finally, in accordance with the results presented here, we demonstrated that the expression of PGC-1 is significantly downregulated in PCa patients and correlates with the increase of ODC expression. Altogether, our results demonstrate that the downregulation of PGC1- regulates an onco-metabolic program implicated in PCa aggressiveness.