Down-regulation of phospho-Akt is a major molecular determinant of bortezomib-induced apoptosis in hepatocellular carcinoma cells
Down-regulation of phospho-Akt is a major molecular determinant of bortezomib-induced apoptosis in hepatocellular carcinoma cells
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DOI：
10.1158/0008-5472.can-08-0257
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发表时间：
2008-08-15
期刊：
影响因子：
11.2
通讯作者：
Cheng, Ann-Lii
中科院分区：
文献类型：
--
作者：
Chen, Kuen-Feng;Yeh, Pei-Yen;Cheng, Ann-Lii
硼替佐米是一种蛋白酶体抑制剂，已被临床批准用于治疗骨髓瘤和淋巴瘤。在这里，我们报告了硼替佐米对四种肝细胞癌（HCC）细胞系细胞凋亡的不同影响，并确定了决定敏感性的主要分子事件。尽管硼替佐米在所有HCC细胞系中抑制蛋白酶体活性的程度相似，但对其活力的影响有所不同：Hub-7 (IC50为196 nmol/L), Sk-Hep1 (IC50为180 nmol/L), Hep3B （IC50为112 nmol/L）和耐药PLC5 （IC50为1000 nmol/L）。硼替佐米在所有HCC细胞中引起G(2)-M期细胞周期阻滞，而凋亡诱导仅在敏感细胞中发现，而在PLC5细胞中没有发现。在hh -7和PLC5中没有观察到硼替佐米诱导的nf - κ B的明显变化。硼替佐米在所有敏感的HCC细胞中均以剂量和时间依赖的方式下调磷酸化akt (P-Akt)，而在PLC5中未发现P-Akt的改变。通过小干扰RNA下调Akt1克服了PLC5细胞对硼替佐米的凋亡抗性，但组成型激活的Akt1保护了hh -7细胞免受硼替佐米诱导的凋亡。此外，硼替佐米在Huh-7肿瘤中显示抑制肿瘤生长，下调P-Akt，而在PLC5肿瘤中没有。P-Akt的下调是硼替佐米诱导HCC细胞系凋亡的主要分子事件，可能是预测HCC治疗临床反应的生物标志物。靶向Akt信号通路克服了肝癌细胞对硼替佐米的耐药，为肝癌的联合治疗提供了新的途径。
Bortezomib, a proteasome inhibitor, has been clinically approved for the treatment of myeloma and lymphoma. Here, we report a differential effect of bortezomib on apoptosis in four hepatocellular carcinoma (HCC) cell lines and identify the major molecular event that determines sensitivity. Although bortezomib inhibited proteasome activity to a similar extent in all HCC cell lines, it showed differential effects on their viability: Hub-7 (IC50 196 nmol/L), Sk-Hep1 (IC50 180 nmol/L), Hep3B (IC50 112 nmol/L), and resistant PLC5 (IC50 > 1,000 nmol/L). Bortezomib caused cell cycle arrest at G(2)-M phase in all HCC cells tested whereas apoptotic induction was found only in sensitive cells but not in PLC5 cells. No significant bortezomib-induced NF-kappa B changes were noted in Huh-7 and PLC5. Bortezomib down-regulated phospho-Akt (P-Akt) in a dose- and time-dependent manner in all sensitive HCC cells whereas no alterations of P-Akt were found in PLC5. Down-regulation of Akt1 by small interference RNA overcame the apoptotic resistance to bortezomib in PLC5 cells, but a constitutively activated Akt1 protected Huh-7 cells from bortezomib-induced apoptosis. Furthermore, bortezomib showed suppression of tumor growth with down-regulation of P-Akt in Huh-7 tumors but not in PLC5 tumors. Down-regulation of P-Akt represents a major molecular event of bortezomib-induced apoptosis in HCC cell lines and may be a biomarker for predicting clinical response to HCC treatment. Targeting Akt signaling overcomes drug resistance to bortezomib in HCC cells, which provides a new approach for the combinational therapy of HCC.