Tumor suppressor p16INK4a − modulator of glycomic profile and galectin‐1 expression to increase susceptibility to carbohydrate‐dependent induction of anoikis in pancreatic carcinoma cells

Expression of the tumor suppressor p16INK4a after stable transfection can restore the susceptibility of epithelial tumor cells to anoikis. This property is linked to increases in the expression and cell‐surface presence of the fibronectin receptor. Considering its glycan chains as pivotal signals, we assumed an effect of p16INK4a on glycosylation. To test this hypothesis for human Capan‐1 pancreatic carcinoma cells, we combined microarray for selected glycosyltransferase genes with 2D chromatographic glycan profiling and plant lectin binding. Major differences between p16‐positive and control cells were detected. They concerned expression of β1,4‐galactosyltransferases (down‐regulation of β1,4‐galactosyltransferases‐I/V and up‐regulation of β1,4‐galactosyltransferase‐IV) as well as decreased α2,3‐sialylation of O‐glycans and α2,6‐sialylation of N‐glycans. The changes are compatible with increased β1‐integrin maturation, subunit assembly and binding activity of the α5β1‐integrin. Of further functional relevance in line with our hypothesis, we revealed differential reactivity towards endogenous lectins, especially galectin‐1. As a result of reduced sialylation, the cells' capacity to bind galectin‐1 was enhanced. In parallel, the level of transcription of the galectin‐1 gene increased conspicuously in p16INK4a‐positive cells, and even figured prominently in a microarray on 1996 tumor‐associated genes and in proteomic analysis. The cells therefore gain optimal responsiveness. The correlation between genetically modulated galectin‐1 levels and anoikis rates in engineered transfectants inferred functional significance. To connect these findings to the fibronectin receptor, galectin‐1 was shown to be co‐immunoprecipitated. We conclude that p16INK4a orchestrates distinct aspects of glycosylation that are relevant for integrin maturation and reactivity to an endogenous effector as well as the effector's expression. This mechanism establishes a new aspect of p16INK4a functionality.

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