Hanker Ariella B, Healy Kevin D, Nichols Jean, Der Channing J
Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
J Mol Signal. 2009 Aug 16;4:5. doi: 10.1186/1750-2187-4-5.
Despite intensive effort, currently no effective anti-Ras therapies have successfully reached clinical application. Previous studies suggest that the histone deacetylatse (HDAC) inhibitor romidepsin, which is currently in clinical trials for the treatment of multiple malignancies, can block Ras-dependent signaling and growth transformation. These studies suggest that mutational activation of Ras may be a useful biomarker for sensitivity to romidepsin and that the anti-tumor activity of this HDAC inhibitor may involve inhibition of Ras effector-mediated signaling.
To rigorously assess romidepsin as an antagonist of Ras, we utilized two well-characterized cell models for Ras transformation. We found that romidepsin blocked the anchorage-dependent and -independent growth of NIH 3T3 fibroblasts and RIE-1 epithelial cells transformed by all three Ras isoforms. However, romidepsin treatment also blocked growth transformation caused by other oncoproteins (B-Raf and ErbB2/Neu), suggesting that romidepsin is not selective for Ras. We also observed striking differences in romidepsin-mediated growth inhibition between transformed NIH 3T3 fibroblasts compared to RIE-1 epithelial cells, suggesting that the mechanism by which romidepsin blocks transformation is dependent on cellular context. Finally, we found that romidepsin did not inhibit Ras activation of the ERK and AKT effector pathways in NIH 3T3 and RIE-1 cells, suggesting that romidepsin does not directly antagonize Ras.
Taken together, our results suggest that romidepsin is not selective for Ras-transformed cells and that the anti-tumor activity of romidepsin is not due to direct inhibition of Ras function.
尽管付出了巨大努力，但目前尚无有效的抗Ras疗法成功应用于临床。先前的研究表明，目前正在进行多种恶性肿瘤治疗临床试验的组蛋白脱乙酰酶（HDAC）抑制剂罗米地辛可阻断Ras依赖性信号传导和生长转化。这些研究表明，Ras的突变激活可能是对罗米地辛敏感性的有用生物标志物，并且这种HDAC抑制剂的抗肿瘤活性可能涉及抑制Ras效应器介导的信号传导。
为了严格评估罗米地辛作为Ras拮抗剂的作用，我们利用了两种特征明确的Ras转化细胞模型。我们发现罗米地辛可阻断由所有三种Ras异构体转化的NIH 3T3成纤维细胞和RIE-1上皮细胞的锚定依赖性和非锚定依赖性生长。然而，罗米地辛处理也阻断了由其他癌蛋白（B-Raf和ErbB2/Neu）引起的生长转化，这表明罗米地辛对Ras没有选择性。我们还观察到，与RIE-1上皮细胞相比，转化的NIH 3T3成纤维细胞在罗米地辛介导的生长抑制方面存在显著差异，这表明罗米地辛阻断转化的机制取决于细胞背景。最后，我们发现罗米地辛在NIH 3T3和RIE-1细胞中不抑制ERK和AKT效应器途径的Ras激活，这表明罗米地辛不直接拮抗Ras。
综上所述，我们的结果表明罗米地辛对Ras转化细胞没有选择性，并且罗米地辛的抗肿瘤活性不是由于直接抑制Ras功能。
