National Center of Excellence for Clinical Trial and Research, Department of Oncology, National Taiwan University Hospital, Graduate Institute of Toxicology, Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Cancer Res. 2010 Nov 15;70(22):9309-18. doi: 10.1158/0008-5472.CAN-10-1033. Epub 2010 Nov 9.
Markers that could accurately predict responses to the general kinase inhibitor sorafenib are needed to better leverage its clinical applications. In this study, we examined a hypothesized role in the drug response for the growth arrest DNA damage-inducible gene 45β (GADD45β), which is commonly underexpressed in hepatocellular carcinoma (HCC) where sorafenib may offer an important new therapeutic option. The anticancer activity of sorafenib-induced GADD45β expression was tested in a panel of HCC cell lines and xenograft models. We found that GADD45β mRNA and protein expression were induced relatively more prominently in HCC cells that were biologically sensitive to sorafenib treatment. GADD45β induction was not found after treatment with either the mitogen-activated protein kinase-extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor U0126 or the Raf inhibitor ZM336372, suggesting that GADD45β induction by sorafenib was independent of Raf/MEK/ERK signaling activity. However, c-Jun NH2-terminal kinase (JNK) kinase activation occurred preferentially in sorafenib-sensitive cells. Small interfering RNA-mediated knockdown of GADD45βor JNK kinase limited the proapoptotic effects of sorafenib in sorafenib-sensitive cells. We defined the -339/-267 region in the GADD45β promoter containing activator protein-1 and SP1-binding sites as a crucial region for GADD45β induction by sorafenib. Together, our findings suggest that GADD45β induction contributes to sorafenib-induced apoptosis in HCC cells, prompting further studies to validate its potential value in predicting sorafenib efficacy.
需要能够准确预测通用激酶抑制剂索拉非尼反应的标志物，以更好地利用其临床应用。在这项研究中，我们研究了生长停滞 DNA 损伤诱导基因 45β（GADD45β）在药物反应中的假设作用，该基因在肝细胞癌（HCC）中通常表达不足，而索拉非尼可能为其提供重要的新治疗选择。在一系列 HCC 细胞系和异种移植模型中测试了索拉非尼诱导的 GADD45β表达的抗癌活性。我们发现，GADD45β mRNA 和蛋白表达在对索拉非尼治疗具有生物学敏感性的 HCC 细胞中相对更为明显地诱导。在用丝裂原激活蛋白激酶-细胞外信号调节激酶（ERK）激酶（MEK）抑制剂 U0126 或 Raf 抑制剂 ZM336372 处理后未发现 GADD45β 诱导，表明 GADD45β 诱导与 Raf/MEK/ERK 信号活性无关。然而，c-Jun NH2-末端激酶（JNK）激酶的激活优先发生在索拉非尼敏感的细胞中。小干扰 RNA 介导的 GADD45β 或 JNK 激酶敲低限制了索拉非尼在索拉非尼敏感细胞中的促凋亡作用。我们将 GADD45β 启动子中包含激活蛋白-1 和 SP1 结合位点的-339/-267 区域定义为 GADD45β 诱导的关键区域。总之，我们的发现表明 GADD45β 诱导有助于 HCC 细胞中索拉非尼诱导的细胞凋亡，促使进一步研究验证其在预测索拉非尼疗效方面的潜在价值。
