title: Regenerating islet-derived family member, 4 modulates multiple receptor tyrosine kinases and mediators of drug resistance in cancer.
abstract: Regenerating islet-derived family member, 4 (Reg IV) is a secreted protein and member of the C-type lectin superfamily. Expression analyses have characterized Reg IV as a prognostic marker for certain cancers; however, the functional role of Reg IV in cancer, including downstream signaling, has only begun to be elucidated. To investigate the biological role of Reg IV in cancer, phosphorylation events were studied in cancer cell lines in the context of either Reg IV stimulation (HCT116 cells) or knockdown of endogenous Reg IV (PC3 and KM12 cells). In addition to the previously observed impact on epidermal growth factor receptor and Akt phosphorylation, we observed modulation in the phosphorylation of multiple additional receptor tyrosine kinases (RTKs), including insulin receptor, insulin-like growth factor receptor as well as their downstream effectors, mitogen-activated protein kinase and phosphatidylinositol-3-kinase pathways. Furthermore, knockdown of Reg IV impacted the ability of insulin and EGF to stimulate downstream tyrosine phosphorylation. Knockdown of Reg IV in cancer cell lines inhibited anchorage-dependent and anchorage-independent (both soft-agar and spheroid assays) cell growth and induced cell cycle arrest. This was accompanied by upregulation of p21 and p27. Transiently silencing Reg IV in cancer cells induced apoptosis and downregulated Bcl-2. Conversely, stimulation of HCT116 cells with recombinant Reg IV induced Bcl-2. Hsp27, a molecule implicated in drug resistance, was similarly modulated by Reg IV. Consistent with our observations with Reg IV siRNA-mediated knockdown, monoclonal antibodies directed against Reg IV inhibited PC3 and KM12 cell growth. Collectively, Reg IV plays an important role in cancer by modulation of key signaling molecules including Hsp27, Bcl-2 and multiple RTKs.
authors: Schering-Plough Biopharma, Palo Alto, CA, USA. kathryn.vanderlaag@novartis.com
authors: Kathryn
authors: K
authors: Vanderlaag
authors: Wei
authors: W
authors: Wang
authors: Laurence
authors: L
authors: Fayadat-Dilman
authors: Janet
authors: J
authors: Wagner
authors: Laura
authors: L
authors: Bald
authors: Jeff
authors: J
authors: Grein
authors: Mary J
authors: MJ
authors: Janatpour
mesh_terms: D017209:Apoptosis / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004815:Epidermal Growth Factor / Q000378:metabolism; D055785:Gene Knockdown Techniques / Q000379:methods; D045325:HCT116 Cells; D057809:HEK293 Cells; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins; D006801:Humans; D007328:Insulin / Q000378:metabolism; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018832:Molecular Chaperones; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D000073718:Pancreatitis-Associated Proteins; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D007328:Insulin; D037181:Lectins, C-Type; D018832:Molecular Chaperones; D000073718:Pancreatitis-Associated Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C428528:REG4 protein, human; D014443:Tyrosine; D004815:Epidermal Growth Factor; D058539:Phosphatidylinositol 3-Kinase; D020794:Receptor Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases