Ganglioside GM3 promotes carcinoma cell proliferation via urokinase plasminogen activator-induced extracellular signal-regulated kinase-independent p70S6 kinase signaling
Ganglioside GM3 promotes carcinoma cell proliferation via urokinase plasminogen activator-induced extracellular signal-regulated kinase-independent p70S6 kinase signaling
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DOI：
10.1038/sj.jid.5700469
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发表时间：
2006-12-01
影响因子：
6.5
通讯作者：
Paller, Amy S.
中科院分区：
文献类型：
--
作者：
Wang, Xiao-Qi;Sun, Ping;Paller, Amy S.
NeuAc α 2-3Gal beta 1-4Glc beta 1-Cer (GM3) 是皮肤肿瘤细胞膜的主要神经节苷脂，其过表达可抑制正常和肿瘤上皮细胞中表皮生长因子 (EGF) 受体的配体依赖性和配体非依赖性激活。这会抑制 Ras/细胞外信号调节激酶 (ERK) 的激活，并且在 EGF 或纤连蛋白存在的情况下，抑制细胞增殖。然而，一些肿瘤细胞表现出GM3水平升高，而针对GM3的疫苗可以抑制体内肿瘤细胞的生长，尤其是黑色素瘤。我们报告说，在尿激酶纤溶酶原激活剂（uPA）存在的情况下，GM3 的过度表达通过增强不依赖于 ERK 的 p70S6 激酶激活来反而增加癌细胞的增殖。功能性阻断 uPA 受体 (uPAR) 或抑制 p70S6 激酶，但不抑制 Ras/ERK 信号传导，可抑制 GM3 诱导的细胞增殖刺激。 p70S6 激酶的 ERK 依赖性激活涉及苏氨酸 389、苏氨酸 421/丝氨酸 424 和丝氨酸 411 位点的磷酸化以及中间磷脂酰肌醇 3 激酶和蛋白激酶 C-tau 的激活。这些研究表明神经节苷脂是 uPAR 相关信号传导的增强剂，并表明对 GM3 的反应取决于 uPA 的局部浓度。针对或补充神经节苷脂的治疗方式可能需要分别抑制 EGFR 或 uPAR 信号传导的同时治疗，以控制肿瘤细胞增殖。
Overexpression of NeuAc alpha 2-3Gal beta 1-4Glc beta 1-Cer (GM3), a major ganglioside of cutaneous tumor cell membranes, inhibits ligand-dependent and ligand-independent activation of the epidermal growth factor (EGF) receptor in normal and neoplastic epithelial cells. This leads to the suppression of Ras/extracellular signal-regulated kinase (ERK) activation and, in the presence of EGF or fibronectin, inhibits cell proliferation. However, some tumor cells show increased levels of GM3, and vaccines that target GM3 can inhibit the growth of neoplastic cells in vivo, especially melanomas. We report that in the presence of urokinase plasminogen activator (uPA), overexpression of GM3 paradoxically increases the proliferation of carcinoma cells by augmenting ERK-independent p70S6 kinase activation. Functional blockade of uPA receptor (uPAR) or inhibition of p70S6 kinase, but not inhibition of Ras/ERK signaling, suppresses this GM3-induced stimulation of cell proliferation. The ERK-independent activation of p70S6 kinase involves phosphorylation at threonine-389, threonine-421/serine-424, and serine-411 sites with intermediate phosphatidylinositol 3 kinase and protein kinase C-tau activation. These studies implicate gangliosides as enhancers of uPAR-related signaling and suggest that the response to GM3 depends on the local concentration of uPA. Therapeutic modalities that target or supplement gangliosides may require concomitant treatment that suppresses EGFR or uPAR signaling, respectively, to control neoplastic cell proliferation.