Hao Honglin, Muniz-Medina Vanessa M, Mehta Heena, Thomas Nancy E, Khazak Vladimir, Der Channing J, Shields Janiel M
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, CB# 7295, Chapel Hill, NC 27599-7295, USA.
Mol Cancer Ther. 2007 Aug;6(8):2220-9. doi: 10.1158/1535-7163.MCT-06-0728.
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 (RNAi) 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 mutation-positive 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 NH(2)-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.
在黑色素瘤和结直肠癌中已观察到Ras及其关键下游效应分子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激活丝裂原活化蛋白激酶（MAPK）/细胞外信号调节激酶激酶（MEK）以及细胞外信号调节激酶MAPK级联反应可能是治疗RAS和B-RAF突变阳性黑色素瘤和结肠癌的有效方法。尽管最近使用干扰RNA（RNAi）和药理抑制剂的研究支持B-Raf信号在黑色素瘤生长中起关键作用，但突变型B-Raf在促进结直肠癌生长中是否具有同等作用尚未确定。在本研究中，我们使用RNAi和药理学方法进一步评估B-Raf激活在人黑色素瘤生长中的作用，并另外确定突变型B-Raf在结直肠癌细胞系中是否也有类似作用。我们观察到，RNAi抑制突变型B-Raf（V600E）表达可强烈抑制B-RAF突变阳性黑色素瘤细胞而非结直肠癌细胞的贴壁依赖性生长。然而，B-RAF突变阳性结直肠癌的非贴壁依赖性和致瘤性生长依赖于突变型B-Raf的功能。最后，MEK和Raf的药理抑制在抑制B-RAF突变阳性黑色素瘤和结直肠癌细胞的生长方面非常有效，而Ras激活的其他蛋白激酶（AKT、c-Jun NH2末端激酶和p38 MAPK）的抑制剂效果较差。我们的观察结果表明，Raf和MEK抑制剂可能对治疗B-RAF突变阳性结直肠癌以及黑色素瘤有效。
