title: Insulin receptor substrate-2 mediated insulin-like growth factor-I receptor overexpression in pancreatic adenocarcinoma through protein kinase Cdelta.
abstract: Pancreatic adenocarcinoma (PCA) is an almost invariably fatal disease. Recently, it has been shown by several groups as well as ours that insulin-like growth factor-I receptor (IGF-IR) overexpression is related to higher proliferation, survival, angiogenesis, and highly invasive pancreatic tumors. Several studies have been carried out to understand the pathways that lead to growth factor-mediated signaling, but the molecular mechanism of receptor overexpression remains mostly unknown. Treatment with neutralizing antibodies or a specific kinase inhibitor against IGF-IR could block the receptor expression in PCA cells. Furthermore, we also showed that insulin receptor substrate (IRS)-2, but not IRS-1, is involved in regulation of IGF-IR expression, which is most likely not transcriptional control. By blocking mammalian target of rapamycin (mTOR) pathway with rapamycin as well as other biochemical analysis, we defined a unique regulation of IGF-IR expression mediated by protein kinase Cdelta (PKCdelta) and mTOR pathway. Moreover, we showed that the down-regulation of IGF-IR expression due to IRS-2 small interfering RNA can be compensated by overexpression of dominant-active mutant of PKCdelta, suggesting that PKCdelta is downstream of IGF-IR/IRS-2 axis. Overall, these findings suggest a novel regulatory role of IRS-2 on the expression of IGF-IR through PKCdelta and mTOR in pancreatic cancer cells.
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Junhye
authors.initials: J
authors.lastname: Kwon
authors.forename: Susann
authors.initials: S
authors.lastname: Stephan
authors.forename: Ananya
authors.initials: A
authors.lastname: Mukhopadhyay
authors.forename: Michael H
authors.initials: MH
authors.lastname: Muders
authors.forename: Shamit K
authors.initials: SK
authors.lastname: Dutta
authors.forename: Julie S
authors.initials: JS
authors.lastname: Lau
authors.forename: Debabrata
authors.initials: D
authors.lastname: Mukhopadhyay
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D002455:Cell Division; D045744:Cell Line, Tumor; D017931:DNA Primers; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000502:physiology*; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D016133:Polymerase Chain Reaction; D014176:Protein Biosynthesis; D051745:Protein Kinase C-delta / Q000235:genetics* / Q000378:metabolism; D011494:Protein Kinases / Q000502:physiology; D012334:RNA, Neoplasm / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D017526:Receptor, IGF Type 1 / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases
chemical_list: D017931:DNA Primers; C526292:IRS1 protein, human; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D011494:Protein Kinases; C546842:MTOR protein, human; D017526:Receptor, IGF Type 1; D058570:TOR Serine-Threonine Kinases; D051745:Protein Kinase C-delta