Insulin receptor substrate is a mediator of phosphoinositide 3-kinase activation in quiescent pancreatic cancer cells

Phosphoinositide 3-kinase (PI3K) is activated in pancreatic cancer cells and plays a central role in their proliferation, survival, and drug resistance. Although the mechanism is unclear, PI3K activation in these cells could be due to physical interaction between its regulatory subunit (p85) and spe...

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Veröffentlicht in:Cancer research (Chicago, Ill.) Ill.), 2005-10, Vol.65 (20), p.9164-9168
Hauptverfasser: ASANO, Takayuki, YIXIN YAO, SHIN, Sonyo, MCCUBREY, James, ABBRUZZESE, James L, REDDY, Shrikanth A. G
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container_issue 20
container_start_page 9164
container_title Cancer research (Chicago, Ill.)
container_volume 65
creator ASANO, Takayuki
YIXIN YAO
SHIN, Sonyo
MCCUBREY, James
ABBRUZZESE, James L
REDDY, Shrikanth A. G
description Phosphoinositide 3-kinase (PI3K) is activated in pancreatic cancer cells and plays a central role in their proliferation, survival, and drug resistance. Although the mechanism is unclear, PI3K activation in these cells could be due to physical interaction between its regulatory subunit (p85) and specific tyrosine kinases or their mediators. Consistent with this possibility, PI3K was precipitated with anti-phosphotyrosine antibodies and Akt phosphorylation was blocked by the tyrosine kinase inhibitors SU6656 and PD158780 in quiescent pancreatic cancer cells. Pull-down assays with a fusion protein (GST-p85NC-SH2), and coimmunoprecipitation studies, indicated that the insulin receptor substrate (IRS), and not the epidermal growth factor and insulin-like growth factor receptors or the Src tyrosine kinase, was physically associated with PI3K in these cells. Our data also indicated that SU6656 and PD158780 inhibited Akt activation in pancreatic cancer cells by interfering with the ability of IRS-1 to recruit PI3K. Furthermore, IRS-1 was phosphorylated on a p85-binding site (Y(612)), and IRS-specific small interfering RNA potently inhibited activation of PI3K and Akt in transfected cells. Taken together, these observations indicate that IRS is a mediator of PI3K activation in quiescent pancreatic cancer cells.
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Pull-down assays with a fusion protein (GST-p85NC-SH2), and coimmunoprecipitation studies, indicated that the insulin receptor substrate (IRS), and not the epidermal growth factor and insulin-like growth factor receptors or the Src tyrosine kinase, was physically associated with PI3K in these cells. Our data also indicated that SU6656 and PD158780 inhibited Akt activation in pancreatic cancer cells by interfering with the ability of IRS-1 to recruit PI3K. Furthermore, IRS-1 was phosphorylated on a p85-binding site (Y(612)), and IRS-specific small interfering RNA potently inhibited activation of PI3K and Akt in transfected cells. 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source MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; American Association for Cancer Research
subjects Biological and medical sciences
Cell Line, Tumor
Enzyme Activation
Gastroenterology. Liver. Pancreas. Abdomen
Humans
Insulin Receptor Substrate Proteins
Liver. Biliary tract. Portal circulation. Exocrine pancreas
Medical sciences
Pancreatic Neoplasms - enzymology
Pancreatic Neoplasms - metabolism
Pancreatic Neoplasms - pathology
Phosphatidylinositol 3-Kinases - metabolism
Phosphoproteins - metabolism
Protein-Tyrosine Kinases - metabolism
Proto-Oncogene Proteins c-akt - metabolism
Receptor, Insulin - metabolism
Tumors
title Insulin receptor substrate is a mediator of phosphoinositide 3-kinase activation in quiescent pancreatic cancer cells
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