Galectin-1 activates carbonic anhydrase IX and modulates glioma metabolism

Abstract

Abstract Galectins are a family of β-galactose-specific binding proteins residing within the cytosol or nucleus, with a highly conserved carbohydrate recognition domain across many species. Accumulating evidence shows that Galectin 1 (Gal-1) plays an essential role in cancer, and its expression correlates with tumor aggressiveness and progression. Our preliminary data showed Gal-1 promotes glioma stem cell (GSC) growth via increased Warburg effect. mRNA expression and clinical data were obtained from The Cancer Genome Atlas database. The immunoblot analysis conducted using our cohort of human glioblastoma patient specimens (hGBM), confirmed Gal-1 upregulation in GBM. GC/MS analysis to evaluate the effects of Gal-1 depletion showed elevated levels of α-ketoglutaric acid, and citric acid with a concomitant reduction in lactic acid levels. Using Biolog microplate-1 mitochondrial functional assay, we confirmed that the depletion of Gal-1 increases the expression levels of the enzymes from the TCA cycle, suggesting a reversal of the Warburg phenotype. Manipulation of Gal-1 using RNA interference showed reduced ATP, lactate levels, cell viability, colony-forming abilities, and increased expression levels of genes implicated in the induction of apoptosis. Gal-1 exerts its metabolic role via regulating the expression of carbonic anhydrase IX (CA-IX), a surrogate marker for hypoxia. CA-IX functions downstream to Gal-1, and co-immunoprecipitation experiments along with proximity ligation assays confirm that Gal-1 physically associates with CA-IX to regulate its expression. Further, silencing of Gal-1 in mice models showed reduced tumor burden and increased survival compared to the mice implanted with GSC controls. Further investigation of Gal-1 in GSC progression and metabolic reprogramming is warranted.