COST Action CA17118 TRANSCOLONCAN Torino Meeting, Turin, Italy, 7 - 09 March 2022, pp.41
Metabolic Rewiring in AKR1B10 Expressing Colorectal Cancer Cells
AKR1B10 is a nicotinamide adenine dinucleotide (phosphate) (NAD(P)H)-dependent reductase enzyme that belongs to the Aldo-Keto Reductase (AKR) 1B subfamily. Although it shares ~70% similarity in amino acid sequence with the AKR1B1 enzyme, unlike AKR1B1, AKR1B10 does not show reductase activity towards glucose. It instead reduces carbonyl-containing compounds such as retinals and lipid-derived cytotoxic aldehydes. We have previously shown that colorectal tumors with high expression of AKR1B1 and low expression of AKR1B10 (AKR1B1HIGH/AKR1B10LOW) could be assigned to Consensus Molecular Subtype (CMS) 4, were associated with enhanced mesenchymal properties and showed significantly poor prognosis. In contrast, the AKR1B1LOW/AKR1B10HIGH signature was primarily epithelial, belonged to CMS3, and was characterized by the inhibition of metabolic pathways associated with biomass production and cell proliferation (Demirkol-Canlı et al., 2020). In the current study, we have focused on metabolic reprogramming in AKR1B10HIGH tumors and cell lines. Cancer cells undergo extensive metabolic reprogramming to fuel cellular growth and proliferation, including increased fatty acid synthesis (FAS). Fatty acid oxidation (FAO) also appears to be essential to supply high amounts of ATP needed by cancer cells. However, what activates FAS versus FAO in cancer cells is a subject of continuing interest. Analyses of publicly available datasets of colorectal tumors showed that AKR1B10 expression, along with FAO genes, was decreased in primary colorectal tumors compared to normal tissues. Furthermore, gene set enrichment analysis of the TCGA-COAD tumors classified into high vs. low AKR1B10 expressing showed that AKR1B10HIGH tumors were enriched in the gene ontology (GO) terms “regulation of lipid metabolism” and “cellular lipid catabolic process”. Stable ectopic expression of AKR1B10 in RKO cells showed robust phosphorylation of Acetyl CoA Carboxylase (ACC). ACC is a regulatory enzyme that undergoes inhibitory phosphorylation when FAO is activated while hypophosphorylation of ACC is associated with increased FAS. Taken together, our findings reveal for the first time that in addition to its role as an oxidoreductase, AKR1B10 expression may regulate lipid metabolism, favoring FAO rather than FAS in colorectal cancer.
Publication: Demirkol Canlı, S., Seza, E. G., Sheraj, I., Gömçeli, I., Turhan, N., Carberry, S., Prehn, J., Güre, A.
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