Extracellular galectin-3 programs multidrug resistance through Na+/K+-ATPase and P-glycoprotein signaling.
Extracellular galectin-3 programs multidrug resistance through Na+/K+-ATPase and P-glycoprotein signaling.
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DOI：
10.18632/oncotarget.4285
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发表时间：
2015-08-14
期刊：
影响因子：
--
通讯作者：
Raz A
中科院分区：
文献类型：
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作者：
Harazono Y;Kho DH;Balan V;Nakajima K;Hogan V;Raz A
半乳糖凝集素-3（Galectin-3，LGALS 3）是一种多效性多功能的29-35 kDa嵌合基因产物，并且参与多种生理和病理过程，包括细胞生长、稳态、凋亡、前体mRNA剪接、细胞-细胞和细胞-基质粘附、细胞极性、运动性、粘附、活化、分化、转化、信号传导、先天/适应性免疫的调节和血管生成。在多种疾病中，发现循环Gal-3的水平显著升高，表明Gal-3依赖性功能是通过与未知的普遍存在的细胞表面蛋白的特异性相互作用介导的。最近，我们发现Gal-3减弱了药物诱导的细胞凋亡，这是多药耐药（MDR）的机制之一。在这里，我们证明MDR可以通过Gal-3与管家基因产物的相互作用介导，Na+/K+-ATP酶和P-糖蛋白（P-gp）。Gal-3与Na+/K+-ATP酶相互作用并诱导P-gp磷酸化。我们还发现Gal-3与P-gp结合并增强其ATP酶活性。此外，Gal-3拮抗剂抑制这种相互作用并导致P-gp的磷酸化和ATP酶活性降低，导致对阿霉素介导的细胞死亡的敏感性增加。总之，这些发现可以解释Gal-3在不同疾病中的报道作用，并表明Na+/K+-ATP酶和Gal-3抑制剂与疾病特异性药物的联合治疗可能上级单一治疗方式。
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.