Vorinostat inhibits STAT6-mediated TH2 cytokine and TARC production and induces cell death in Hodgkin lymphoma cell lines
Vorinostat inhibits STAT6-mediated TH2 cytokine and TARC production and induces cell death in Hodgkin lymphoma cell lines
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DOI：
10.1182/blood-2008-01-133769
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发表时间：
2008-08-15
期刊：
影响因子：
20.3
通讯作者：
Younes, Anas
中科院分区：
文献类型：
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作者：
Buglio, Daniela;Georgakis, Georgios V.;Younes, Anas
在霍奇金淋巴瘤(HL)的霍奇金细胞和Reed-Sternberg细胞(HRS)中，表观遗传学改变导致了一些B细胞基因的沉默，这一机制被认为是促进HRS存活和逃避免疫监视的机制。然而，组蛋白脱乙酰酶(HDAC)抑制在HL中的分子和功能后果以前还没有被描述。在这项研究中，我们报告了HDAC抑制剂Vorinostat诱导p21表达并降低BCI-xl水平，导致细胞周期停滞和细胞凋亡。此外，伐力诺以剂量和时间依赖的方式抑制STAT6的磷酸化并降低其mRNA水平，这与胸腺和活化调节趋化因子(TARC/CCL17)和白介素5(IL-5)的表达和分泌减少以及IP-10水平升高有关。此外，VORINO-STAT抑制胸腺基质淋巴生成素(TSLP)激活的树突状细胞分泌TARC。综上所述，这些数据表明，药物抑制HL中的HDAC可能通过直接抑制HRS细胞的增殖而产生良好的抗肿瘤活性，并可能通过改变微环境中细胞因子和趋化因子的分泌而产生免疫调节效应。
Epigenetic changes have been implicated in silencing several B-cell genes in Hodgkin and Reed-Sternberg cells (HRS) of Hodgkin lymphoma (HL), and this mechanism has been proposed to promote HRS survival and escape from immunosurveillance. However, the molecular and functional consequences of histone deacetylase (HDAC) inhibition in HL have not been previously described. In this study, we report that the HDAC inhibitor vorinostat induced p2l expression and decreased BcI-xL levels causing cell-cycle arrest and apoptosis. Furthermore, vorinostat inhibited STAT6 phosphorylation and decreased its mRNA levels in a dose- and time-dependent manner, which was associated with a decrease in the expression and secretion of Thymus and Activation-Regulated Chemokine (TARC/CCL17) and interleukin (IL)-5 and an increase in IP-10 levels. Moreover, vorino-stat inhibited TARC secretion by dendritic cells that were activated by the thymic stromal lymphopoietin (TSLP). Collectively, these data suggest that pharmacologic HDAC inhibition in HL may induce favorable antitumor activity by a direct antiproliferative effect on HRS cells, and possibly by an immune mediated effect by altering cytokine and chemokines secretion in the microenvironment.