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Insulin Receptor Substrate-2 Mediated Insulin-like Growth Factor-I Receptor Overexpression in Pancreatic Adenocarcinoma through Protein Kinase C

Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota

Requests for reprints: Debabrata Mukhopadhyay, Department of Biochemistry and Molecular Biology, Gugg 1401A, Mayo Clinic College of Medicine, 200 First Street Southwest, Rochester, MN 55905. Phone: 507-538-3581; Fax: 507-284-1767; E-mail: mukhopadhyay.debabrata{at}mayo.edu.

Key Words: IGF-IR • protein expression • PKC • mTOR • TSC2 • pancreatic cancer

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 C (PKC) 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 PKC, suggesting that PKC 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 PKC and mTOR in pancreatic cancer cells. [Cancer Res 2009;69(4):1350–7]