2012年8月30日 訊 /生物谷BIOON/ --在肝癌中，肝細(xì)胞是過表達(dá)缺氧誘導(dǎo)因子（HIF）-1α的,，HIF-1α導(dǎo)致血管生成和肝癌患者預(yù)后較差,。索拉非尼是一種多激酶抑制劑，已經(jīng)在臨床試驗中證明能顯著改善晚期肝癌患者生存率,。然而,，索拉非尼的抗血管生成機(jī)制尚未完全闡明。一項最新發(fā)表在Clinical Cancer Research雜志上的研究旨在探討索拉非尼對肝癌細(xì)胞和異種移植肝癌細(xì)胞HIF-1α表達(dá)和活化的影響,。
該研究采用Western印跡法和定量PCR陣列分別用來確定HIF-1α蛋白及mRNA的表達(dá)情況,。HIF-1α蛋白的合成、HIF-1α蛋白的活性以及血管內(nèi)皮生長因子的分泌均采用檢測試劑盒測定,。結(jié)果證實索拉非尼劑量依賴性地降低了缺氧誘導(dǎo)的HIF-1α蛋白的表達(dá)和活化,。
進(jìn)一步分析顯示，索拉非尼減少HIF-1α的表達(dá)與抑制HIF-1α蛋白的合成相關(guān),，而不是通過促進(jìn)HIF-1α蛋白降解或抑制HIF-1αmRNA來實現(xiàn)的,。此外，mTOR,、ERK等蛋白的磷酸化水平顯著被索拉非尼抑制,。
體內(nèi)研究進(jìn)一步證實索拉非尼對HIF-1α和VEGF蛋白的表達(dá)具有抑制作用，導(dǎo)致腫瘤血管形成減少以及異種移植的腫瘤生長受到抑制,。臨床前數(shù)據(jù)證實索拉非尼抗血管生成機(jī)制是通過抑制HIF-1α和VEGF蛋白表達(dá)來實現(xiàn)的,。（生物谷：Bioon.com）
doi:10.1158/1078-0432.CCR-12-0552
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Sorafenib inhibits hypoxia-inducible factor-1α synthesis: implications for anti-angiogenic activity in hepatocellular carcinoma
Li-ping Liu, Rocky LK Ho, George G Chen,*, and Paul Lai
Purpose:The overexpression of hypoxia-inducible factor (HIF)-1α is a common finding in hepatocellular carcinoma (HCC), and it leads to angiogenesis and poor prognosis. Sorafenib, a multikinase inhibitor, has demonstrated significant improvement in survival in patients with advanced HCC in clinical trials. However, the mechanisms that account for the anti-angiogenic efficiency of sorafenib have not been fully elucidated. The present study aims to explore the effect of sorafenib on HIF-1α expression and activation in HCC cells and xenografts. Experimental Design:HCC cells and xenografts were treated with sorafenib or vehicles. Western blotting and qPCR array were employed to determine protein and mRNA expression, respectively. HIF-1α activity, de novo protein synthesis and VEGF secretions were determined using assay kits. Results:Sorafenib dose-dependently decreased the hypoxia-induced accumulation and activation of HIF-1α protein. Further analysis revealed that such reduction of HIF-1α was associated with the inhibition of HIF-1α protein synthesis rather than the promotion of HIF-1α protein degradation or the reduction of HIF-1α mRNA. Moreover, the phosphorylation levels of mTOR, ERK, p70S6K, RP-S6, 4E-BP1 and eIF4E were significantly suppressed by sorafenib. In vivo studies further confirmed the inhibitory effect of sorafenib on the expression of HIF-1α and VEGF proteins, leading to a decrease in tumor vascularisation and growth of the xenografts. Conclusions:Sorafenib-mediated inhibition of HIF-1α synthesis is associated with previously undefined pathways in which mTOR/p70S6K/4E-BP1 and ERK phosphorylation are downregulated. Our preclinical data expand our understanding of sorafenib's anti-angiogenic mechanism of action by inhibiting HIF-1α and VEGF protein expression.
