TCA cycle nutrient use and invasiveness of ovarian cancer (WP2868)

Homo sapiens

Schematic showing the shift in nutrient utilization in TCA cycle with increasing degree of invasiveness. Low-invasive ovarian cancer (OVCA) cells are glucose dependent for their TCA cycle pool. With increasing invasiveness in cancer cells, dominant nutrient which feeds the TCA cycle shifts from glucose to Gln. In high-invasive OVCA cells, Gln dominates the TCA cycle. In low-invasive OVCA cells, glucose activates Jak1, which activates STAT3 by tyrosine phosphorylation, thereby regulating glycolysis in cancer cells. In highinvasive OVCA cells, besides glucose's role in activating STAT3 tyrosine phosphorylation, glutamine activates JAK1 through TCA cycle to further activate STAT3 by tyrosine phosphorylation and thus regulate glycolysis. Further, Gln activates Erk1/2, which subsequently activates STAT3 by serine phosphorylation selectively in high-invasive OVCA cells. The serine phosphorylation of STAT3 enhances oxidative phosphorylation in mitochondria by interaction with mitochondrial complexes I and II, thereby increasing TCA cycle activity in high-invasive OVCA cells. Protein phosphorylation sites were added based on information from PhosphoSitePlus (R), Proteins on this pathway have targeted assays available via the [ CPTAC Assay Portal]


Kristina Hanspers , Martina Summer-Kutmon , Alex Pico , Denise Slenter , Friederike Ehrhart , Eric Weitz , and Egon Willighagen


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Homo sapiens


CPTAC Diseases ExRNA


Pathway Ontology

cancer pathway altered citric acid cycle pathway

Disease Ontology

ovarian cancer reproductive system disease cancer


Label Type Compact URI Comment
Lactate Metabolite hmdb:HMDB0000190
D-Glutamine Metabolite hmdb:HMDB0003423
Pyruvate Metabolite hmdb:HMDB0000243
Glucose Metabolite hmdb:HMDB0000122
Glucose Metabolite hmdb:HMDB0000122
Glucose Metabolite hmdb:HMDB0000122
STAT3 GeneProduct ncbigene:6774
ERK1 GeneProduct ncbigene:5595
JAK1 GeneProduct ncbigene:3716
ERK2 GeneProduct ncbigene:5594
EGFR GeneProduct ncbigene:1956
STAT3 GeneProduct ncbigene:6774
EGFR GeneProduct ncbigene:1956
JAK1 GeneProduct ncbigene:3716
STAT3 GeneProduct ncbigene:6774


  1. Metabolic shifts toward glutamine regulate tumor growth, invasion and bioenergetics in ovarian cancer. Yang L, Moss T, Mangala LS, Marini J, Zhao H, Wahlig S, et al. Mol Syst Biol. 2014 May 5;10(5):728. PubMed Europe PMC Scholia
  2. PhosphoSitePlus, 2014: mutations, PTMs and recalibrations. Hornbeck PV, Zhang B, Murray B, Kornhauser JM, Latham V, Skrzypek E. Nucleic Acids Res. 2015 Jan;43(Database issue):D512-20. PubMed Europe PMC Scholia