The molecular determinants of de novo nucleotide biosynthesis in cancer cells

Abstract

Summary Tumor cells increase the use of anabolic pathways to satisfy the metabolic requirements associated with a high growth rate. Transformed cells take up and metabolize nutrients such as glucose and glutamine at high levels that support anabolic growth. Oncogenic signaling through the PI3K/Akt and Myc pathways directly control glucose and glutamine uptake, respectively. In order to achieve elevated rates of nucleotide biosynthesis, neoplastic cells must divert carbon from PI3K/Akt-induced glycolytic flux into the non-oxidative branch of the pentose phosphate pathway to generate ribose 5-phosphate. This redirection of glucose catabolism appears to be regulated by cytoplasmic tyrosine kinases. Myc-induced glutamine metabolism also increases the abundance and activity of different rate-limiting enzymes that produce the molecular precursors required for de novo nucleotide synthesis. In this review, we will focus on recent progress in understanding of how glucose and glutamine metabolism is redirected by oncogenes in order to support de novo nucleotide biosynthesis during proliferation and how metabolic reprogramming can be potentially exploited in the development of new cancer therapies.

Nrf2, but not β‐catenin, mutation represents an early event in rat hepatocarcinogenesis

“…1A,B). Twenty-four of 25 Nrf2 mutations were located in the Nrf2 regions coding for either the LxxQDxDLG motif (spanning amino acids [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] or the DxETGE motif (amino acids 77-82) (Fig. 1C).…”

“…28,29 In this context, it is interesting to note that Nrf2, other than maintaining redox homeostasis in quiescent cells, is able to redirect glucose metabolism into anabolic pathways 30 ; indeed, while increased Nrf2 expression shifts glucose distribution toward purine nucleotide synthesis (through activation of the pentose phosphate pathway), Nrf2 knockdown inhibits this process. 30 Even if the impact of Nrf2/Keap1 activation on the hepatocyte pentose phosphate pathway is unknown, it is conceivable that Nrf2-induced expression of this pathway may account (1) for the aggressive proliferation of Nrf2-overexpressing cells, by providing purines required for nucleic acid synthesis, and (2) for increased survival due to its ability to generate antioxidant species.…”

Pharmacological targeting of guanosine monophosphate synthase suppresses melanoma cell invasion and tumorigenicity

“…Melanoma and other cancers cells have been shown to strongly rely on de novo nucleotide biosynthesis 4,5 and often overexpress several biosynthetic enzymes involved in these pathways. [6][7][8][9] Recently, we have identified a fundamental connection between melanoma invasion and biosynthesis of guanylates, 8 suggesting that distortion of the guanylate metabolism facilitates melanoma progression.…”

L’effet Warburg

“…La toxicité de ces molécules sur le métabolisme des cellules normales en phase proliférative peut cependant limiter leur utilisation [35]. Des essais cliniques étudiant l'efficacité de la metformine dans le traitement de différents cancers sont en cours [43] cellules néoplasiques dérivent le flux glycolytique vers la branche non oxydative de la voie des pentoses phosphates pour produire le ribose-5-phosphate [37]. La synthèse de novo d'acides gras facilite la production de lipides qui régulent l'activité de différents oncogènes.…”