title: Extracellular galectin-3 programs multidrug resistance through Na+/K+-ATPase and P-glycoprotein signaling.
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.
authors.affiliation: Departments of Oncology and Pathology, School of Medicine, Wayne State University, and Karmanos Cancer Institute, Detroit, MI 48201, USA.|Department of Maxillofacial Surgery, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Harazono
authors.affiliation: Departments of Oncology and Pathology, School of Medicine, Wayne State University, and Karmanos Cancer Institute, Detroit, MI 48201, USA.
authors.forename: Dhong Hyo
authors.initials: DH
authors.lastname: Kho
authors.affiliation: Everon Biosciences, Buffalo, NY 14203, USA.
authors.forename: Vitaly
authors.initials: V
authors.lastname: Balan
authors.affiliation: Departments of Oncology and Pathology, School of Medicine, Wayne State University, and Karmanos Cancer Institute, Detroit, MI 48201, USA.
authors.forename: Kosei
authors.initials: K
authors.lastname: Nakajima
authors.affiliation: Departments of Oncology and Pathology, School of Medicine, Wayne State University, and Karmanos Cancer Institute, Detroit, MI 48201, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Hogan
authors.affiliation: Departments of Oncology and Pathology, School of Medicine, Wayne State University, and Karmanos Cancer Institute, Detroit, MI 48201, USA.
authors.forename: Avraham
authors.initials: A
authors.lastname: Raz
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001798:Blood Proteins; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D004789:Enzyme Activation; D005260:Female; D037502:Galectin 3 / Q000378:metabolism* / Q000494:pharmacology; D037161:Galectins; D006367:HeLa Cells; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D010766:Phosphorylation; D011485:Protein Binding; D040901:Proteomics / Q000379:methods; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000903:Antibiotics, Antineoplastic; D001798:Blood Proteins; D037502:Galectin 3; D037161:Galectins; C428445:LGALS3 protein, human; D004317:Doxorubicin; D019061:src-Family Kinases; C499076:ATP1A1 protein, human; D000254:Sodium-Potassium-Exchanging ATPase
keywords: Na+/K+-ATPase; P-glycoprotein; galectin-3; multidrug resistance; phosphorylation