Research Papers:

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

Yosuke Harazono _, Dhong Hyo Kho, Vitaly Balan, Kosei Nakajima, Victor Hogan and Avraham Raz

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Oncotarget. 2015; 6:19592-19604. https://doi.org/10.18632/oncotarget.4285

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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

Correspondence to:

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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