Context-dependent roles of mutant B-Raf signaling in melanoma and colorectal carcinoma cell growth
Context-dependent roles of mutant B-Raf signaling in melanoma and colorectal carcinoma cell growth
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DOI：
10.1158/1535-7163.mct-06-0728
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发表时间：
2007-08-01
影响因子：
5.7
通讯作者：
Shields, Janiel M.
中科院分区：
文献类型：
--
作者：
Hao, Honglin;Muniz-Medina, Vanessa M.;Shields, Janiel M.
在黑色素瘤和结直肠癌中已经观察到RAS和RAS的关键下游效应因子B-Raf丝氨酸/苏氨酸激酶的突变激活。这些观察结果表明，抑制B-Raf活化的丝裂原活化蛋白激酶(MAPK)/细胞外信号调节激酶(MEK)和细胞外信号调节激酶MAPK级联通路可能是治疗RAS和B-RAF突变阳性黑色素瘤和结肠癌的有效途径。虽然最近对干扰RNA(RNAP)和药物抑制剂的研究支持B-Raf信号在黑色素瘤生长中的关键作用，但突变的B-Raf是否在促进结直肠癌生长方面具有同等作用尚未确定。在这项研究中，我们使用RNAi和药理学方法来进一步评估B-Raf激活在人类黑色素瘤生长中的作用，并另外确定突变的B-Raf是否在结直肠癌细胞系中也有类似的作用。我们观察到，突变的B-Raf(V600E)表达的RNAi抑制强烈地抑制了B-Raf突变阳性黑色素瘤细胞的锚定依赖性生长，但不抑制结直肠癌细胞。然而，B-RAF突变阳性结直肠癌的锚定非依赖性和致瘤性生长依赖于突变的B-Raf功能。MEK和Raf的药理抑制对B-RAF突变阳性黑色素瘤和结直肠癌细胞的生长有显著的抑制作用，而RAS激活的其他蛋白激酶的抑制剂(AKT、c-jun氨基末端激酶和p38MAPK)的作用较弱。我们的观察表明，Raf和MEK抑制剂可能对B-RAF突变阳性的结直肠癌和黑色素瘤有效。
Mutational activation of Ras and a key downstream effector of Ras, the B-Raf serine/threonine kinase, has been observed in melanomas and colorectal carcinomas. These observations suggest that inhibition of B-Raf activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase kinase (MEK) and the extracellular signal-regulated kinase MAPK cascade may be an effective approach for the treatment of RAS and B-RAF mutation-positive melanomas and colon carcinomas. Although recent studies with interfering RNA (RNAP and pharmacologic inhibitors support a critical role for B-Raf signaling in melanoma growth, whether mutant B-Raf has an equivalent role in promoting colorectal carcinoma growth has not been determined. In the present study, we used both RNAi and pharmacologic approaches to further assess the role of B-Raf activation in the growth of human melanomas and additionally determined if a similar role for mutant B-Raf is seen for colorectal carcinoma cell lines. We observed that RNAi suppression of mutant B-Raf (V600E) expression strongly suppressed the anchorage-dependent growth of B-RAF mutation-positive melanoma, but not colorectal carcinoma, cells. However, the anchorage-independent and tumorigenic growth of B-RAF mutationpositive colorectal carcinomas was dependent on mutant B-Raf function. Finally, pharmacologic inhibition of MEK and Raf was highly effective at inhibiting the growth of B-RAF mutation-positive melanomas and colorectal carcinoma cells, whereas inhibitors of other protein kinases activated by Ras (AKT, c-Jun NH2-terminal kinase, and p38 MAPK) were less effective. Our observations suggest that Raf and MEK inhibitors may be effective for the treatment of B-RAF mutation-positive colorectal carcinomas as well as melanomas.