Insulin receptor substrate-2 mediated insulin-like growth factor-I receptor overexpression in pancreatic adenocarcinoma through protein kinase Cδ

Junhye Kwon, Susann Stephan, Ananya Mukhopadhyay, Michael H. Muders, Shamit K. Dutta, Julie S. Lau, Debabrata Mukhopadhyay

Research output: Contribution to journalArticle

25 Scopus citations

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 Cδ (PKCδ) 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 PKCS, suggesting that PKCδ 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 PKCS and mTOR in pancreatic cancer cells.

Original languageEnglish (US)
Pages (from-to)1350-1357
Number of pages8
JournalCancer research
Volume69
Issue number4
DOIs
StatePublished - Feb 15 2009

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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