Tumor suppressor p16^INK4a: Downregulation of galectin‐3, an endogenous competitor of the pro‐anoikis effector galectin‐1, in a pancreatic carcinoma model

Abstract

The tumor suppressor p16INK4a has functions beyond cell‐cycle control via cyclin‐dependent kinases. A coordinated remodeling of N‐ and O‐glycosylation, and an increase in the presentation of the endogenous lectin galectin‐1 sensing these changes on the surface of p16INK4a‐expressing pancreatic carcinoma cells (Capan‐1), lead to potent pro‐anoikis signals. We show that the p16INK4a‐dependent impact on growth‐regulatory lectins is not limited to galectin‐1, but also concerns galectin‐3. By monitoring its expression in relation to p16INK4a status, as well as running anoikis assays with galectin‐3 and cell transfectants with up‐ or downregulated lectin expression, a negative correlation between anoikis and the presence of this lectin was established. Nuclear run‐off and northern blotting experiments revealed an effect of the presence of p16INK4a on steady‐state levels of galectin‐3‐specific mRNA that differed from decreasing the transcriptional rate. On the cell surface, galectin‐3 interferes with galectin‐1, which initiates signaling toward its pro‐anoikis activity via caspase‐8 activation. The detected opposite effects of p16INK4a at the levels of growth‐regulatory galectins‐1 and ‐3 shift the status markedly towards the galectin‐1‐dependent pro‐anoikis activity. A previously undescribed orchestrated fine‐tuning of this effector system by a tumor suppressor is discovered.

Identification of Galectin-1 and Galectin-3 as Novel Partners for Von Willebrand Factor

“…However, it has been reported that Gal-1 and Gal-3 may have differential effects on ligand binding. 38,39 The possibility exists, therefore, that more pronounced effects on thrombus formation could be observed in single-knockout mice. …”

Galectin-1 Couples Glycobiology to Inflammation in Osteoarthritis through the Activation of an NF-κB–Regulated Gene Network

“…On the biochemical side, counterreceptor characterization, for the protein/ lipid and its glycosylation, will define the first steps of the trigger cascade, from initial binding to signaling. In fact, Galectin-1 is known to target only few glycoconjugates despite the abundance of b-galactosides on the cell surface, the a 5 b 1 -integrin being especially relevant for growth regulation (56), and p16 INK4a -dependent reprogramming of counterreceptor expression and glycosylation may serve as precedent (27,28,57). That the counterreceptor(s), on the level of the protein and/or its glycosylation, may be subject to NF-kB-dependent regulation, as is the case for CD7 (a glycoprotein counterreceptor in apoptosis induction of activated T cells) in murine L7 lymphoma cells (58), is a tempting assumption.…”

Les galectines

“…La découverte d'agents thérapeutiques actifs contre les galectines n'en est qu'à ses prémices. Pour être efficaces tout en limitant les effets secondaires, les drogues antigalectines devront être sélectives d'une ou de plusieurs galectines qui peuvent avoir des effets antagonistes, par exemple pro-ou anti-anoïkis 1 [33], voire être spécifiques de la forme extra ou intracellulaire d'une galectine. Leur action devra être locale plutôt que systémique, et les voies d'administration ou de ciblage appropriées.…”