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. Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP2868 CPTAC Assay Portal]

Authors

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

Cited In

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Organism

Homo sapiens

Communities

CPTAC Diseases

Annotations

Pathway Ontology: altered citric acid cycle pathway cancer pathway

Disease Ontology: cancer reproductive system disease ovarian cancer

Participants

Label	Type	Compact Identifier
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

References

1. Yang L, Moss T, Mangala LS, Marini J, Zhao H, Wahlig S, et al. Metabolic shifts toward glutamine regulate tumor growth, invasion and bioenergetics in ovarian cancer. Mol Syst Biol. 2014 May 5;10(5):728. PubMed Europe PMC Scholia