HDAC2 deficiency sensitizes colon cancer cells to TNFα-induced apoptosis through inhibition of NF-κB activity
HDAC2 deficiency sensitizes colon cancer cells to TNFα-induced apoptosis through inhibition of NF-κB activity
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DOI：
10.1016/j.yexcr.2008.01.010
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发表时间：
2008-04-15
影响因子：
3.7
通讯作者：
Klampfer, Lidija
中科院分区：
文献类型：
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作者：
Kaler, Pawan;Sasazuki, Takehiko;Klampfer, Lidija
HDAC抑制剂发挥有效的抗肿瘤和抗炎活性。他们的作用是选择性的转化细胞，我们最近证明，转化上皮细胞与k-Ras敏感细胞HDACi诱导的细胞凋亡。本研究的目的是确定HDACi通过主要促炎细胞因子TNF α调节信号传导的能力是否也限于含有突变型k-Ras的细胞。我们使用了两个同基因细胞系的系统，这两个细胞系的不同之处在于突变型k-Ras的存在，HCT 116和Hke 3细胞。单独用TNF α处理细胞不诱导细胞凋亡;然而HDACi在HCT 116和Hke 3细胞中都增强了TNF α诱导的细胞凋亡。因此，HDACi使细胞对TNF α诱导的细胞凋亡敏感的能力似乎不依赖于k-Ras。我们证明HDACi抑制TNF α诱导的NF-κ B B转录和DNA结合活性在两种细胞系中，在用两种药剂处理的细胞中增加的凋亡的基础。我们发现HDAC 2的过表达增强了TNF α诱导的NF-κ B活性，而HDAC 2的沉默降低了NF-κ B活性。最后，HDAC 2表达的沉默足以使结肠癌细胞对TNF α诱导的凋亡敏感。HDACi干扰NF-κ B活性的能力可能有助于其有效的抗肿瘤和抗炎活性。(C)2008年爱思唯尔公司All rights reserved.
HDAC inhibitors exert potent anti-tumorigenic and anti-inflammatory activity. Their effects are selective for transformed cells, and we recently demonstrated that transformation of epithelial cells with k-Ras sensitizes cells to HDACi induced apoptosis. The aim of this study was to determine whether the ability of HDACi to modulate signaling by a major proinflammatory cytokine, TNF alpha, is also restricted to cells that harbor mutant k-Ras. We used the system of two isogenic cell lines that differ by the presence of mutant k-Ras, HCT116 and Hke3 cells. Treatment of cells with TNF alpha alone did not induce apoptosis; however HDACi potentiated TNF alpha-induced apoptosis in both HCT116 and Hke3 cells. Thus, the ability of HDACi to sensitize cells to TNF alpha-induced apoptosis appears to be k-Ras independent. We demonstrated that HDACi inhibited TNFa-induced NF-kappa B transcriptional and DNA binding activity in both cell lines, underlying the increased apoptosis in cells treated with both agents. We showed that overexpression of HDAC2 enhanced TNFa-induced NF-kappa B activity and that silencing of HDAC2 decreased NF-kappa B activity. Finally, silencing of HDAC2 expression was sufficient to sensitize colon cancer cells to TNF alpha-induced apoptosis. The ability of HDACi to interfere with NF-kappa B activity is likely to contribute to their potent anti-tumorigenic and anti-inflammatory activity. (C) 2008 Elsevier Inc. All rights reserved.