Abstract
Galectin-3 (Gal-3, LGALS3) is a pleotropic versatile, 29-35 kDa chimeric gene product, and involved in diverse physiological and pathological processes, including cell growth, homeostasis, apoptosis, pre-mRNA splicing, cell-cell and cell-matrix adhesion, cellular polarity, motility, adhesion, activation, differentiation, transformation, signaling, regulation of innate/adaptive immunity, and angiogenesis. In multiple diseases, it was found that the level of circulating Gal-3 is markedly elevated, suggesting that Gal-3-dependent function is mediated by specific interaction with yet an unknown ubiquitous cell-surface protein. Recently, we showed that Gal-3 attenuated drug-induced apoptosis, which is one of the mechanisms underlying multidrug resistance (MDR). Here, we document that MDR could be mediated by Gal-3 interaction with the house-keeping gene product e.g., Na+/K+-ATPase, and P-glycoprotein (P-gp). Gal-3 interacts with Na+/K+-ATPase and induces the phosphorylation of P-gp. We also find that Gal-3 binds P-gp and enhances its ATPase activity. Furthermore Gal-3 antagonist suppresses this interaction and results in a decrease of the phosphorylation and the ATPase activity of P-gp, leading to an increased sensitivity to doxorubicin-mediated cell death. Taken together, these findings may explain the reported roles of Gal-3 in diverse diseases and suggest that a combined therapy of inhibitors of Na+/K+-ATPase and Gal-3, and a disease specific drug(s) might be superior to a single therapeutic modality.
Highlights
Galectins are a family of mammalian beta-galactoside binding proteins that share a highly conserved carbohydrate recognition domain (CRD) of which 15 galectin members have been identified to date [1, 2]
We recently showed that the anti-apoptotic function of intracellular Gal-3 in which its expression increased with cis-diammineplatinum dichloride (CDDP) and doxorubicin hydrochloride (DXR) treatment [25]
The endogenous Na+/K+-ATPase was co-precipitated with Gal-3-V5 regardless of cancer cell type, and the reciprocal experiments revealed that Gal3-V5 was co-immunoprecipitated with Na+/K+-ATPase (Figure 2B)
Summary
Galectins are a family of mammalian beta-galactoside binding proteins that share a highly conserved carbohydrate recognition domain (CRD) of which 15 galectin members have been identified to date [1, 2]. Galectin-3 (Gal-3) is the only member of the chimera-type galectin subgroup and contains a single CRD. There is both direct and circumstantial evidence that Gal-3 plays a significant role in cell growth, homeostasis, apoptosis, pre-mRNA splicing, adhesion, activation, differentiation, transformation, signaling, angiogenesis, inflammation, fibrosis, cancer progression, and metastasis [3,4,5,6,7,8]. It was reported that the level of circulating Gal-3 is significantly elevated in the serum of patients with various cancers [9,10, 11]. The interaction of Gal-3 with carbohydrate-conjugates of cell surface proteins and components of the extracellular matrix (ECM) such as MUC1, CD98, laminin and fibronectin, results in tumor cell migration, invasion and metastasis [14,15,16]
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