Contrasting Effects of the Cytotoxic Anticancer Drug Gemcitabine and the EGFR Tyrosine Kinase Inhibitor Gefitinib on NK Cell-Mediated Cytotoxicity via Regulation of NKG2D Ligand in Non-Small-Cell Lung Cancer Cells.
Contrasting Effects of the Cytotoxic Anticancer Drug Gemcitabine and the EGFR Tyrosine Kinase Inhibitor Gefitinib on NK Cell-Mediated Cytotoxicity via Regulation of NKG2D Ligand in Non-Small-Cell Lung Cancer Cells.
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DOI：
10.1371/journal.pone.0139809
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Nakata M
中科院分区：
文献类型：
--
作者：
Okita R;Wolf D;Yasuda K;Maeda A;Yukawa T;Saisho S;Shimizu K;Yamaguchi Y;Oka M;Nakayama E;Lundqvist A;Kiessling R;Seliger B;Nakata M
一些细胞毒性抗癌药物抑制DNA复制和/或有丝分裂，而EGFR酪氨酸激酶抑制剂使癌细胞中的EGFR信号失活。这两种类型的抗癌药物都提高了非小细胞肺癌（NSCLC）患者的总生存率，尽管肿瘤对这种治疗往往变得难治性。尽管已经描述了肿瘤产生耐药性的几种机制，但这些化合物对抗肿瘤免疫的影响在很大程度上仍然未知。本研究探讨了细胞毒性药物吉西他滨和EGFR酪氨酸激酶抑制剂吉非替尼对NK组2成员D （NKG2D）配体表达的影响以及NSCLC细胞对NK介导的裂解的敏感性。我们证明吉西他滨治疗导致表达增强，而吉非替尼下调作为激活受体NKG2D的关键配体的分子的表达，并促进NK细胞介导的识别和细胞溶解。吉西他滨激活ATM和ATM-和rad -3相关蛋白激酶（ATR）途径。吉西他滨诱导的ATM磷酸化和NKG2D配体表达上调可以被ATM- atr抑制剂阻断。相反，吉非替尼降低了NKG2D配体的表达。使用siRNA沉默EGFR或添加PI3K抑制剂可导致NKG2D配体的下调。这些观察结果表明，EGFR/PI3K通路也调节NKG2D配体的表达。此外，我们发现ATM-ATR和EGFR都通过miR20a调节MICA/B。与对NKG2D表达的影响一致，吉西他滨增强NK细胞介导的细胞毒性，而吉非替尼减弱NK细胞在NSCLC细胞中的杀伤作用。
Several cytotoxic anticancer drugs inhibit DNA replication and/or mitosis, while EGFR tyrosine kinase inhibitors inactivate EGFR signalling in cancer cell. Both types of anticancer drugs improve the overall survival of the patients with non-small-cell lung cancer (NSCLC), although tumors often become refractory to this treatment. Despite several mechanisms by which the tumors become resistant having been described the effect of these compounds on anti-tumor immunity remains largely unknown. This study examines the effect of the cytotoxic drug Gemcitabine and the EGFR tyrosine kinase inhibitor Gefitinib on the expression of NK group 2 member D (NKG2D) ligands as well as the sensitivity of NSCLC cells to the NK-mediated lysis. We demonstrate that Gemcitabine treatment leads to an enhanced expression, while Gefitinib downregulated the expression of molecules that act as key ligands for the activating receptor NKG2D and promote NK cell-mediated recognition and cytolysis. Gemcitabine activated ATM and ATM- and Rad-3-related protein kinase (ATR) pathways. The Gemcitabine-induced phosphorylation of ATM as well as the upregulation of the NKG2D ligand expression could be blocked by an ATM-ATR inhibitor. In contrast, Gefitinib attenuated NKG2D ligand expression. Silencing EGFR using siRNA or addition of the PI3K inhibitor resulted in downregulation of NKG2D ligands. The observations suggest that the EGFR/PI3K pathway also regulates the expression of NKG2D ligands. Additionally, we showed that both ATM-ATR and EGFR regulate MICA/B via miR20a. In keeping with the effect on NKG2D expression, Gemcitabine enhanced NK cell-mediated cytotoxicity while Gefitinib attenuated NK cell killing in NSCLC cells.
影响因子：
7.2
作者：
Kiessling R;Okita R;Mougiakakos D;Mao Y;Sarhan D;Wennerberg E;Seliger B;Lundqvist A;Mimura K;Kono K
通讯作者：
Kono K