Department of Biochemistry, Pusan National University School of Medicine, Yangsan, South Korea.
J Immunother. 2011 May;34(4):372-81. doi: 10.1097/CJI.0b013e31821b724a.
As quercetin, which can inhibit phosphatidylinositol 3-kinase, nuclear factor-kappa B, and protein kinase C (PKC) pathways, induced expression of natural killer group 2, member D (NKG2D) ligands on cancer cells and made the cells sensitive to NK -cell-mediated killing; inhibition of epidermal growth factor receptor (EGFR) pathway might lead to induction of NKG2D ligands. In this study, it was investigated whether EGFR inhibitors, including erlotinib or gefitinib, could regulate expression of NKG2D ligands in various lung cancer cells including A549, NCI-H23, and SW-900. The EGFR inhibitors predominantly increased transcription and surface expression of ULBP1, and subsequently increased susceptibility of the cancer cells to NK-92 cells. When the selective inhibitors of nuclear factor-kappa B, phosphatidylinositol 3-kinase, mitogen-activated protein kinases, and PKC were treated to discriminate downstream signaling of EGFR pathway, expression of ULBP1 in the cancer cells was induced by inhibition of PKC. Treatment with phorbol 12-myristate 13-acetate restored the EGFR inhibitor-induced ULBP1 transcription. Binding activity to ULBP1 promoter region of AP-2α, which suggested as suppressor of expression of ULBP1, was decreased by treatment with EGFR inhibitors, and restored by pretreatment with phorbol 12-myristate 13-acetate in A549 and SW-900. Rottlerin, a PKCδ inhibitor, also decreased the binding activity of AP-2α in dose-dependent manner. This study suggests that EGFR inhibitors enhanced the susceptibility to NK cell-mediated lysis of lung cancer cells by induction of ULBP1 by inhibition of PKC pathway and therapeutic efficacy of EGFR inhibitors in lung cancer may be mediated in part by increased susceptibility to NK cell-mediated cytotoxicity.
槲皮素可抑制磷脂酰肌醇 3-激酶、核因子-κB 和蛋白激酶 C（PKC）通路，诱导癌细胞表达自然杀伤细胞组 2 成员 D（NKG2D）配体，使细胞对 NK 细胞介导的杀伤敏感；抑制表皮生长因子受体（EGFR）通路可能导致 NKG2D 配体的诱导。在这项研究中，研究了包括厄洛替尼或吉非替尼在内的 EGFR 抑制剂是否可以调节包括 A549、NCI-H23 和 SW-900 在内的各种肺癌细胞中 NKG2D 配体的表达。EGFR 抑制剂主要增加 ULBP1 的转录和表面表达，随后增加癌细胞对 NK-92 细胞的敏感性。当使用核因子-κB、磷脂酰肌醇 3-激酶、丝裂原活化蛋白激酶和 PKC 的选择性抑制剂来区分 EGFR 通路的下游信号时，通过抑制 PKC 诱导癌细胞中 ULBP1 的表达。用佛波醇 12-肉豆蔻酸 13-乙酸酯处理以恢复 EGFR 抑制剂诱导的 ULBP1 转录。与 ULBP1 启动子区域结合的活性，AP-2α，提示为 ULBP1 表达的抑制剂，通过 EGFR 抑制剂处理降低，并通过佛波醇 12-肉豆蔻酸 13-乙酸酯预处理在 A549 和 SW-900 中恢复。PKCδ抑制剂罗特林以剂量依赖的方式也降低了 AP-2α 的结合活性。这项研究表明，EGFR 抑制剂通过抑制 PKC 通路诱导 ULBP1 的表达增强了肺癌细胞对 NK 细胞介导的裂解的敏感性，EGFR 抑制剂在肺癌中的治疗效果可能部分通过增加对 NK 细胞介导的细胞毒性的敏感性来介导。
