Gatla Himavanth R, Zou Yue, Uddin Mohammad M, Singha Bipradeb, Bu Pengli, Vancura Ales, Vancurova Ivana
From the Department of Biological Sciences, St. John's University, New York, New York 11439 and.
The Wistar Institute, Philadelphia, Pennsylvania 19104.
J Biol Chem. 2017 Mar 24;292(12):5043-5054. doi: 10.1074/jbc.M116.771014. Epub 2017 Feb 6.
Overexpression of the pro-angiogenic chemokine IL-8 (CXCL8) is associated with a poor prognosis in several solid tumors, including epithelial ovarian cancer (EOC). Even though histone deacetylase (HDAC) inhibition has shown remarkable antitumor activity in hematological malignancies, it has been less effective in solid tumors, including EOC. Here we report results that may explain the decreased efficiency of HDAC inhibition in EOC, based on our data demonstrating that HDAC inhibition specifically induces expression of IL-8/CXCL8 in SKOV3, CAOV3, and OVCAR3 cells. Suppression or neutralization of vorinostat-induced IL-8/CXCL8 potentiates the vorinostat inhibitory effect on cell viability and proliferation. The IL-8/CXCL8 expression induced by vorinostat in EOC cells is dependent on IκB kinase (IKK) activity and associated with a gene-specific recruitment of IKKβ and IKK-dependent recruitment of p65 NFκB to the IL-8/CXCL8 promoter. In addition, HDAC inhibition induces acetylation of p65 and histone H3 and their IL-8/CXCL8 promoter occupancy. results demonstrate that combining vorinostat and the IKK inhibitor Bay 117085 significantly reduces tumor growth in nude mice compared with control untreated mice or either drug alone. Mice in the combination group had the lowest IL-8/CXCL8 tumor levels and the lowest tumor expression of the murine neutrophil [7/4] antigen, indicating reduced neutrophil infiltration. Together, our results demonstrate that HDAC inhibition specifically induces IL-8/CXCL8 expression in EOC cells and that the mechanism involves IKK, suggesting that using IKK inhibitors may increase the effectiveness of HDAC inhibitors when treating ovarian cancer and other solid tumors characterized by increased IL-8/CXCL8 expression.
促血管生成趋化因子白细胞介素8（IL-8，即CXCL8）的过表达与包括上皮性卵巢癌（EOC）在内的多种实体瘤的不良预后相关。尽管组蛋白去乙酰化酶（HDAC）抑制在血液系统恶性肿瘤中显示出显著的抗肿瘤活性，但在包括EOC在内的实体瘤中效果较差。在此，我们报告的结果可能解释了HDAC抑制在EOC中效率降低的原因，基于我们的数据表明HDAC抑制可特异性诱导SKOV3、CAOV3和OVCAR3细胞中IL-8/CXCL8的表达。伏立诺他诱导的IL-8/CXCL8的抑制或中和增强了伏立诺他对细胞活力和增殖的抑制作用。伏立诺他在EOC细胞中诱导的IL-8/CXCL8表达依赖于IκB激酶（IKK）活性，并与IKKβ的基因特异性募集以及p65核因子κB（NFκB）依赖IKK募集到IL-8/CXCL8启动子相关。此外，HDAC抑制诱导p65和组蛋白H3的乙酰化及其对IL-8/CXCL8启动子的占据。结果表明，与未治疗的对照小鼠或单独使用任何一种药物相比，伏立诺他与IKK抑制剂Bay 117,085联合使用可显著降低裸鼠肿瘤生长。联合治疗组小鼠的肿瘤IL-8/CXCL8水平最低，小鼠中性粒细胞[7/4]抗原的肿瘤表达最低，表明中性粒细胞浸润减少。总之，我们的结果表明HDAC抑制可特异性诱导EOC细胞中IL-8/CXCL8表达，其机制涉及IKK，这表明在治疗卵巢癌和其他以IL-8/CXCL8表达增加为特征的实体瘤时，使用IKK抑制剂可能会提高HDAC抑制剂的有效性。
