title: EGFR inhibitors enhanced the susceptibility to NK cell-mediated lysis of lung cancer cells.
abstract: 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.
authors.affiliation: Department of Biochemistry, Pusan National University School of Medicine, Yangsan, South Korea.
authors.forename: Hyunsu
authors.initials: H
authors.lastname: Kim
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Kim
authors.forename: Mi-Ju
authors.initials: MJ
authors.lastname: Kim
authors.forename: So-Jung
authors.initials: SJ
authors.lastname: Kim
authors.forename: Soo-Jung
authors.initials: SJ
authors.lastname: Park
authors.forename: Joo-Seop
authors.initials: JS
authors.lastname: Chung
authors.forename: Jae-Ho
authors.initials: JH
authors.lastname: Bae
authors.forename: Chi-Dug
authors.initials: CD
authors.lastname: Kang
mesh_terms: D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D008175:Lung Neoplasms / Q000276:immunology; D011493:Protein Kinase C / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D050656:Transcription Factor AP-2 / Q000378:metabolism
chemical_list: D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D050656:Transcription Factor AP-2; C423231:ULBP1 protein, human; C423230:ULBP2 protein, human; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D011493:Protein Kinase C; D000077156:Gefitinib