Inhibition of MAPK kinase signaling pathways suppressed renal cell carcinoma growth and angiogenesis in vivo
Inhibition of MAPK kinase signaling pathways suppressed renal cell carcinoma growth and angiogenesis in vivo
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DOI：
10.1158/0008-5472.can-07-5311
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发表时间：
2008-01-01
期刊：
影响因子：
11.2
通讯作者：
Teh, Bin Tean
中科院分区：
文献类型：
--
作者：
Huang, Dan;Ding, Yan;Teh, Bin Tean
丝裂原活化蛋白激酶（MAPK）信号通路在细胞增殖和分化中起重要作用。最近的研究还表明MAPK信号通路在多种人类恶性肿瘤（包括肾细胞癌（RCC））的肿瘤发生、转移和血管生成中被激活。为了评估该通路在调节RCC细胞增殖和存活中的作用，我们首先检测了透明细胞RCC中MAPK激酶（MKK）和MAPK的表达，并证实了MKK 1和细胞外信号调节激酶2（ERK 2）在这些肿瘤中的过表达。然后，我们使用炭疽致死毒素（LeTx）在体外和体内测试了MKK对人RCC细胞系的药理学抑制作用，该毒素可切割并灭活几种MKK。Western blotting显示72 μ l LeTx处理后ERK、c-Jun-NH 2激酶和p38 MAPK的磷酸化水平降低。暴露于LeTx 72，其使细胞增殖降低20%，而对细胞周期分布和凋亡没有显著影响。肾癌细胞的锚定非依赖性生长显着抑制LeTx。体内研究表明，肾细胞癌异种移植瘤的生长可以抑制LeTx。LeTx治疗后观察到广泛坏死和肿瘤新生血管减少。LeTx在体外也显示出直接抑制内皮细胞的增殖。我们的研究结果表明，抑制一个或多个MAPK信号通路可能通过破坏肿瘤血管抑制RCC生长。
The mitogen-activated protein kinase (MAPK) signaling pathways play essential roles in cell proliferation and differentiation. Recent studies also show the activation of MAPK signaling pathways in tumorigenesis, metastasis, and angiogenesis of multiple human malignancies, including renal cell carcinoma (RCC). To assess the role of this pathway in regulating the proliferation and survival of RCC cells, we first examined the expression of MAPK kinase (MKK) and MAPK in clear cell RCC and confirmed the overexpression of MKK1 and extracellular signal-regulated kinase 2 (ERK2) in these tumors. We then tested the effects of pharmacologic inhibition of MKK on human RCC cell lines, both in vitro and in vivo, using anthrax lethal toxin (LeTx), which cleaves and inactivates several MKKs. Western blotting showed that the phosphorylation levels of ERK, c-Jun-NH2 kinase, and p38 MAPK decreased after 72 It of LeTx treatment. Exposure to LeTx for 72 It reduced cell proliferation by 20% without significant effects on cell cycle distribution and apoptosis. Anchorage-independent growth of RCC cells was dramatically inhibited by LeTx. In vivo studies showed that tumor growth of RCC xenografts could be suppressed by LeTx. Extensive necrosis and decreased tumor neovascularization were observed after LeTx treatment. LeTx also showed direct inhibition of proliferation of endothelial cells in vitro. Our results suggest that suppression of one or more MAPK signaling pathways may inhibit RCC growth through the disruption of tumor vasculature.