Regenerating islet-derived family member, 4 modulates multiple receptor tyrosine kinases and mediators of drug resistance in cancer

Autor: Janet Wagner, Mary J. Janatpour, Kathryn E. Vanderlaag, Laura Bald, Wei Wang, Laurence Fayadat-Dilman, Jeff Grein
Rok vydání: 2011
Předmět:
Cancer Research
Cell signaling
HSP27 Heat-Shock Proteins
Apoptosis
Pancreatitis-Associated Proteins
chemical and pharmacologic phenomena
Cell Growth Processes
Receptor tyrosine kinase
chemistry.chemical_compound
Growth factor receptor
immune system diseases
Cell Line
Tumor
Neoplasms
Humans
Insulin
Lectins
C-Type
Epidermal growth factor receptor
Phosphorylation
Heat-Shock Proteins
Epidermal Growth Factor
biology
Cell Cycle
Receptor Protein-Tyrosine Kinases
hemic and immune systems
Tyrosine phosphorylation
Cell Cycle Checkpoints
HCT116 Cells
Up-Regulation
Insulin receptor
HEK293 Cells
Proto-Oncogene Proteins c-bcl-2
Oncology
chemistry
Drug Resistance
Neoplasm
Gene Knockdown Techniques
biology.protein
Cancer research
Tyrosine
Mitogen-Activated Protein Kinases
Phosphatidylinositol 3-Kinase
Signal transduction
Molecular Chaperones
Signal Transduction
Zdroj: International Journal of Cancer. 130:1251-1263
ISSN: 0020-7136
Popis: 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.
Databáze: OpenAIRE
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