Modulation of pro- and anti-apoptotic factors in human melanoma cells exposed to histone deacetylase inhibitors
Modulation of pro- and anti-apoptotic factors in human melanoma cells exposed to histone deacetylase inhibitors
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DOI：
10.1023/b:appt.0000038036.31271.50
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发表时间：
2004-09-01
期刊：
影响因子：
7.2
通讯作者：
La Porta, CAM
中科院分区：
文献类型：
--
作者：
Facchetti, F;Previdi, S;La Porta, CAM
丙戊酸(VPA，2-丙基戊酸)是一种公认的长期治疗癫痫的药物。最近，VPA被证明在治疗相关的浓度下抑制组蛋白脱乙酰基酶(HDACs)I类酶，从而模仿典型的组蛋白脱乙酰基酶抑制剂Tricostatin A(TSA)或Suberoylanilide草酮酸(SAHA)。在本研究中，我们研究了VPA、TSA和SAHA对四种人黑色素瘤细胞系(WM115、WM266、A375、SK-Mel28)的细胞作用，特别是对凋亡调节因子Bcl2、BclXL、Mcl-1、APAF-1、BclXs、NOXA、TRAIL-R1、TRAIL-R2、caspase 8和Survivin的调节作用。首先，我们发现丙戊酸能诱导四种人黑色素瘤细胞株中的两种发生凋亡，而TSA和SAHA对这四种细胞均具有抗增殖和诱导凋亡的作用，但Bcl一2和Bclx的表达有所不同(L/S)。另一方面，SAHA和VPA对促凋亡和抗凋亡因子的调节不同。特别是，VPA处理只上调VPA耐药细胞株中Survivin的表达水平，而VPA和SAHA诱导VPA敏感细胞中Survivin表达下调。在后者中，由于caspase8被证明是激活的，因此提出了受体介导的细胞凋亡。综上所述，我们的结果表明，HDAC抑制剂可能是治疗黑色素瘤的一种有前途的治疗策略。
Valproic acid (VPA, 2-propylpentanoic acid) is an established drug in the long-term therapy of epilepsy. Recently, VPA was demonstrated to inhibit histone deacetylases (HDACs) class I enzyme at therapeutically relevant concentrations, thereby, mimicking the prototypical histone deacetylase inhibitors, tricostatin A (TSA) or suberoylanilide hydroxamic acid (SAHA). In the present study, we investigated the cellular effects of VPA, TSA and SAHA on four human melanoma cell lines (WM115, WM266, A375, SK-Mel28) with particular reference to the modulation of regulators of apoptosis, including Bcl-2, BclXL, Mcl-1, Apaf-1, BclXs, NOXA, TRAIL-R1, TRAIL-R2, caspase 8, and survivin). Firstly, we found that VPA induced apoptosis in two of the four human melanoma cell lines, while both TSA and SAHA exhibited an antiproliferative and apoptotic effects in all four cell lines, a different expression of Bcl-2 and BclX(L/S) occurred. On the other hand, SAHA and VPA modulated differently pro- and anti-apoptotic factors. In particular, the treatment with VPA enhanced the level of expression of survivin only in VPA-resistant cell lines, whereas down-regulation of survivin was induced by VPA and SAHA in VPA-sensitive cells. In the latter, since activation of caspase 8 was documented, a receptor-mediated apoptosis was suggested. Taken together, our results suggest that HDAC inhibitors may represent a promising therapeutic strategy to treat melanoma.