Targeting β2-microglobulin mediated signaling as a novel therapeutic approach for human renal cell carcinoma
Targeting β2-microglobulin mediated signaling as a novel therapeutic approach for human renal cell carcinoma
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DOI：
10.1016/j.juro.2007.03.007
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发表时间：
2007-07-01
影响因子：
6.6
通讯作者：
Chung, Leland W. K.
中科院分区：
文献类型：
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作者：
Nomura, Takeo;Huang, Wen-Chin;Chung, Leland W. K.
目的：我们以前报道过β2-微球蛋白的生物学功能包括抗原递呈和致癌活性。在本研究中，我们研究了β2-微球蛋白在人肾癌细胞生长调控中的直接作用，以及用抗β2-微球蛋白中和抗体阻断β2-微球蛋白信号通路可能的诱导凋亡作用。材料和方法：我们检测了重组β2-微球蛋白和抗β2-微球蛋白抗体对体外培养的肾癌细胞生长和凋亡的影响。为了从分子水平上了解抗β2-微球蛋白抗体诱导SN12C细胞凋亡的机制，我们在SN12C细胞中应用相应的激酶抑制剂，分析了磷脂酰肌醇3-激酶/Akt、细胞外信号调节蛋白和c-jun氨基末端激酶途径中生长和存活信号成分的变化。结果：重组β2-微球蛋白以剂量和时间依赖的方式促进3种人肾癌细胞株SN12C、Caki-1和ACHN的生长。用抗β2微球蛋白多克隆抗体处理SN12C、Caki-1和ACHN细胞，在体外对这些细胞的生长有强烈的抑制作用，且呈剂量和时间依赖性。重组β2-微球蛋白或抗β2-微球蛋白抗体分别增加或降低SN12C细胞的贴壁非依赖性生长。重组β2-微球蛋白通过激活磷脂酰肌醇3-激酶/Akt和胞外信号调节蛋白来促进细胞生长，并诱导与Bclxl/Bcl2相关的死亡启动子的磷酸化。然而，抗β2微球蛋白抗体通过抑制Akt和细胞外信号调节激酶的磷酸化，激活c-jun氨基末端激酶，诱导B细胞淋巴瘤2的磷酸化，降低Bc1-xl/Bcl2相关死亡启动子的磷酸化，导致细胞凋亡。结论：抗β2微球蛋白抗体在调节肾癌细胞的生长和存活中具有重要作用，为肾癌的治疗提供了一种新的治疗方法。
Purpose: We previously reported that the biological functions of beta 2-microglobulin include antigen presentation and oncogenic activity. In the current study we investigated the direct role of beta 2-microglobulin in the regulation of human renal cell carcinoma cell growth and the possible apoptotic inducing effect of blocking the beta 2-microglobulin signaling pathway using an anti-beta 2-microglobulin neutralizing antibody.Materials and Methods: We examined the effects of recombinant beta 2-microglobulin protein and anti-beta 2-microglobulin antibody on renal cell carcinoma cell growth and apoptosis in vitro. To seek a molecular understanding of anti-beta 2-microglobulin antibody induced apoptosis we analyzed alterations in the growth and survival signaling components in the phosphatidylinositol 3-kinase/Akt, extracellular signal-regulated kinase and c-jun N-terminal kinase mediated pathways using corresponding kinase inhibitors in SN12C cells.Results: Recombinant beta 2-microglobulin protein increased the growth of the 3 human renal cell carcinoma cell lines SN12C, Caki-1 and ACHN in a dose and time dependent manner. Treatment of SN12C, Caki-1 and ACHN cells with an anti-beta 2-microglobulin polyclonal antibody strongly suppressed the growth of these cells in vitro, also in a dose and time dependent manner. The addition of recombinant beta 2-microglobulin protein or anti-beta 2-microglobulin antibody increased or decreased, respectively, the anchorage independent growth of SN12C cells. The recombinant beta 2-microglobulin protein accelerated cell growth via activating phosphatidylinositol 3-kinase/Akt and extracellular signal-regulated kinase, and induced the phosphorylation of Bcl-xL/Bcl-2-associated death promoter. However, treatment with anti-beta 2-microglobulin antibody induced cell death by inhibiting the phosphorylation of Akt and extracellular signal-regulated kinase, and activating c-jun N-terminal kinase, resulting in the induction of phosphorylation of B-cell lymphoma 2 and decreased phosphorylation of Bc1-xL/Bcl-2-associated death promoter, leading to apoptosis.Conclusions: Our results demonstrate that beta 2-microglobulin has an important role in regulating the growth and survival of renal cell carcinoma cells and anti-beta 2-microglobulin antibody offers a potential novel therapy for the treatment of human renal cell carcinoma.