Susceptibility to natural killer cell-mediated lysis of colon cancer cells is enhanced by treatment with epidermal growth factor receptor inhibitors through UL16-binding protein-1 induction
Susceptibility to natural killer cell-mediated lysis of colon cancer cells is enhanced by treatment with epidermal growth factor receptor inhibitors through UL16-binding protein-1 induction
复制标题
DOI：
10.1111/j.1349-7006.2011.02109.x
复制
发表时间：
2012-01-01
期刊：
影响因子：
5.7
通讯作者：
Kang, Chi-Dug
中科院分区：
文献类型：
--
作者：
Bae, Jae-Ho;Kim, So-Jung;Kang, Chi-Dug
我们之前的研究表明，槲皮素抑制细胞内信号通路可诱导癌细胞上自然杀伤细胞群2D （NKG2D）配体的表达，并使细胞对自然杀伤细胞（NK）介导的细胞毒性敏感。在本研究中，我们研究了表皮生长因子受体（EGFR）抑制剂是否可以诱导结肠癌细胞中NKG2D配体的表达。使用EGFR抑制剂治疗主要增加了各种结肠癌细胞（包括表达EGFR的KM12、cco -2、HCT-15和HT-29）中ul16结合蛋白-1 (ULBP1) mRNA转录物和表面蛋白的水平，并增加了这些结肠癌细胞对NK-92细胞的易感性。ULBP1的表达不受核因子- jb、磷脂酰肌醇3激酶和MAPK抑制剂的诱导，而受PKC抑制剂的诱导，并且在结肠癌细胞中，PMA可以阻止EGFR抑制剂诱导ULBP1的表达。一种对ULBP1转录具有抑制作用的转录因子，激活蛋白-2 α (AP-2a)，通过使用EGFR抑制剂阻止了与ULBP1启动子的结合。本研究表明，EGFR抑制剂可以通过抑制PKC通路诱导ULBP1，从而增强NK细胞介导的结肠癌细胞裂解的易感性。（癌症科学2012；103:7-16）
We have previously shown that inhibition of intracellular signaling pathways by treatment with quercetin induced the expression of natural killer cell group 2D (NKG2D) ligands on cancer cells and made the cells sensitive to natural killer (NK)-cell mediated cytotoxicity. In the present study, we investigated whether epidermal growth factor receptor (EGFR) inhibitors could induce the expression of NKG2D ligands in colon cancer cells. Treatment with EGFR inhibitors predominantly increased the levels of mRNA transcripts and surface protein of UL16-binding protein-1 (ULBP1) in various colon cancer cells, including KM12, Caco-2, HCT-15, and HT-29, which express EGFR, and increased susceptibility of these colon cancer cells to NK-92 cells. The expression of ULBP1 was not induced by inhibitors of nuclear factor-jB, phosphatidylinositol 3 kinase, and MAPK, but was induced by inhibitors of PKC, and the induction of ULBP1 expression with EGFR inhibitors was prevented by treatment with PMA in colon cancer cells. A transcription factor, activator protein-2 alpha (AP-2a), which has a suppressive effect on ULBP1 transcription, was prevented from binding to the ULBP1 promoter by treatment with EGFR inhibitors. The present study suggests that EGFR inhibitors can enhance the susceptibility to NK cell-mediated lysis of colon cancer cells by induction of ULBP1 via inhibition of the PKC pathway. (Cancer Sci 2012; 103: 7-16)