title: Susceptibility to natural killer cell-mediated lysis of colon cancer cells is enhanced by treatment with epidermal growth factor receptor inhibitors through UL16-binding protein-1 induction.
abstract: 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-κB, 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-2α), 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.
authors.affiliation: Department of Biochemistry, Pusan National University School of Medicine, Yangsan, South Korea.
authors.forename: Jae-Ho
authors.initials: JH
authors.lastname: Bae
authors.forename: So-Jung
authors.initials: SJ
authors.lastname: Kim
authors.forename: Mi-Ju
authors.initials: MJ
authors.lastname: Kim
authors.forename: Sae-Ock
authors.initials: SO
authors.lastname: Oh
authors.forename: Joo-Seop
authors.initials: JS
authors.lastname: Chung
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Kim
authors.forename: Chi-Dug
authors.initials: CD
authors.lastname: Kang
mesh_terms: D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D005434:Flow Cytometry; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D058851:GPI-Linked Proteins; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D012333:RNA, Messenger; C423231:ULBP1 protein, human; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib