Extracellular galectin-3 programs multidrug resistance through Na+/K+-ATPase and P-glycoprotein signaling.

// Yosuke Harazono 1, 2 , Dhong Hyo Kho 1 , Vitaly Balan 3 , Kosei Nakajima 1 , Victor Hogan 1 , Avraham Raz 1 1 Departments of Oncology and Pathology, School of Medicine, Wayne State University, and Karmanos Cancer Institute, Detroit, MI 48201, USA 2 Department of Maxillofacial Surgery, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan 3 Everon Biosciences, Buffalo, NY 14203, USA Correspondence to: Avraham Raz, e-mail: raza@karmanos.org Keywords: galectin-3, Na+/K+-ATPase, multidrug resistance, P-glycoprotein, phosphorylation Received: May 13, 2015      Accepted: June 05, 2015      Published: June 17, 2015 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.