Extracellular galectin-3 programs multidrug resistance through Na+/K+-ATPase and P-glycoprotein signaling
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Yosuke Harazono1,2, Dhong Hyo Kho1, Vitaly Balan3, Kosei Nakajima1, Victor Hogan1, Avraham Raz1
1Departments of Oncology and Pathology, School of Medicine, Wayne State University, and Karmanos Cancer Institute, Detroit, MI 48201, USA
2Department of Maxillofacial Surgery, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan
3Everon Biosciences, Buffalo, NY 14203, USA
Avraham Raz, e-mail: [email protected]
Keywords: galectin-3, Na+/K+-ATPase, multidrug resistance, P-glycoprotein, phosphorylation
Received: May 13, 2015 Accepted: June 05, 2015 Published: June 17, 2015
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.
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