T-cell receptor gene therapy targeting melanoma-associated antigen-A4 inhibits human tumor growth in non-obese diabetic/SCID/γcnull mice
T-cell receptor gene therapy targeting melanoma-associated antigen-A4 inhibits human tumor growth in non-obese diabetic/SCID/γcnull mice
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DOI：
10.1111/j.1349-7006.2011.02111.x
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发表时间：
2012-01-01
期刊：
影响因子：
5.7
通讯作者：
Shiku, Hiroshi
中科院分区：
文献类型：
--
作者：
Shirakura, Yoshitaka;Mizuno, Yukari;Shiku, Hiroshi
我们先前已经表明，通过用槲皮素处理来抑制细胞内信号传导途径诱导癌细胞上自然杀伤细胞组2D（NKG 2D）配体的表达，并使细胞对自然杀伤（NK）细胞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NKG 2D配体的表达。EGFR抑制剂治疗主要增加了各种结肠癌细胞（包括表达EGFR的KM 12、Caco-2、HCT-15和HT-29）中UL 16结合蛋白-1（ULBP 1）的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。ULBP 1的表达不诱导核因子-？B、磷脂酰肌醇3激酶和MAPK，但由PKC抑制剂诱导，并且在结肠癌细胞中用PMA处理阻止了用EGFR抑制剂诱导ULBP 1表达。通过用EGFR抑制剂处理来防止对ULBP 1转录具有抑制作用的转录因子激活蛋白-2 α（AP-2a）与ULBP 1启动子结合。目前的研究表明，EGFR抑制剂可以通过抑制PKC途径诱导ULBP 1来增强对NK细胞介导的结肠癌细胞溶解的易感性。（Cancer Sci 2012; 103：716）
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-?B, 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: 716)