RRC ID 65430
著者 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.
タイトル 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.
ジャーナル PLoS One
Abstract INTRODUCTION: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.
METHODS: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.
RESULTS: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.
CONCLUSION:In keeping with the effect on NKG2D expression, Gemcitabine enhanced NK cell-mediated cytotoxicity while Gefitinib attenuated NK cell killing in NSCLC cells.
巻・号 10(10)
ページ e0139809
公開日 2015-1-1
DOI 10.1371/journal.pone.0139809
PII PONE-D-14-51573
PMID 26439264
PMC PMC4595469
MeSH Antineoplastic Agents / pharmacology* Carcinoma, Non-Small-Cell Lung / immunology Carcinoma, Non-Small-Cell Lung / metabolism* Carcinoma, Non-Small-Cell Lung / pathology Cell Line, Tumor Cell Proliferation / drug effects Cytotoxicity, Immunologic / drug effects* Deoxycytidine / analogs & derivatives* Deoxycytidine / pharmacology ErbB Receptors / antagonists & inhibitors Gefitinib Gemcitabine Humans Killer Cells, Natural / immunology Killer Cells, Natural / metabolism* Killer Cells, Natural / pathology Lung Neoplasms / immunology Lung Neoplasms / metabolism* Lung Neoplasms / pathology NK Cell Lectin-Like Receptor Subfamily K / genetics NK Cell Lectin-Like Receptor Subfamily K / metabolism* Protein Kinase Inhibitors / pharmacology* Quinazolines / pharmacology*
IF 2.74
リソース情報
ヒト・動物細胞 RERF-LC-AI(RCB0444) RERF-LC-KJ(RCB1313) LC-2/ad(RCB0440) A549