Galectin-3 regulates a molecular switch from N-Ras to K-Ras usage in human breast carcinoma cells
Galectin-3 regulates a molecular switch from N-Ras to K-Ras usage in human breast carcinoma cells
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DOI：
10.1158/0008-5472.can-05-0775
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发表时间：
2005-08-15
期刊：
影响因子：
11.2
通讯作者：
Kloog, Y
中科院分区：
文献类型：
--
作者：
Shalom-Feuerstein, R;Cooks, T;Kloog, Y
半乳糖凝集素-3（Galectin-3，Gal-3）是一种多效性碳水化合物结合蛋白，是活化的K-Ras-GTP的选择性结合伴侣。因为这两种蛋白质都是抗凋亡的，并且与癌症进展相关，我们质疑Gal-3在K-Ras激活中可能的功能作用。我们发现人乳腺癌细胞（BT-549/Gal-3）中Gal-3的过表达与野生型（wt）K-Ras-GTP的显著增加以及wt N-Ras-GTP的缺失相一致，而非致癌Gal-3突变蛋白[Gal-3（S6 E）和Gal-3（G182 A）]未能诱导Ras同种型转换。只有野生型Gal-3蛋白与致癌K-Ras共免疫沉淀和共定位，导致其激活，Ras信号通路发生根本性改变，从而抑制AKT和Ral的激活并转移到细胞外信号调节激酶（ERK）的激活。Ras或丝裂原活化蛋白/ERK激酶的特异性抑制剂（分别为法尼基硫代水杨酸和U 0126）抑制Gal-3介导的凋亡抗性和锚定非依赖性生长功能。总之，本研究表明，Gal-3赋予BT-549人乳腺癌细胞几个致癌功能，通过结合和激活野生型K-Ras，这表明Gal-3的一些分子功能，至少部分，K-Ras激活的结果。
Galectin-3 (Gal-3), a pleiotropic carbohydrate-binding protein, is a selective binding partner of activated K-Ras-GTP. Because both proteins are antiapoptotic and associated with cancer progression, we questioned the possible functional role of Gal-3 in K-Ras activation. We found that overexpression of Gal-3 in human breast cancer cells (BT-549/Gal-3) coincided with a significant increase in wild-type (wt) K-Ras-GTP coupled with loss in wt N-Ras-GTP, whereas the nononcogenic Gal-3 mutant proteins [Gal-3(S6E) and Gal-3(G182A)] failed to induce the Ras isoform switch. Only wt Gal-3 protein coimmunoprecipitated and colocalized with oncogenic K-Ras, resulting in its activation with radical alterations in Ras signaling pathway, whereby the activation of AKT and Ral was suppressed and shifted to the activation of extracellular signal-regulated kinase (ERK). Specific inhibitors for Ras or mitogen-activated protein/ERK kinase (farnesylthiosalicylic acid and U0126, respectively) inhibited Gal-3-mediated apoptotic resistance and anchorage-independent growth functions. In conclusion, this study shows that Gal-3 confers on BT-549 human breast carcinoma cells several oncogenic functions by binding to and activation of wt K-Ras, suggesting that some of the molecular functions of Gal-3 are, at least in part, a result of K-Ras activation.