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Dopamine, by Acting through Its D2 Receptor, Inhibits Insulin-Like Growth Factor-I (IGF-I)-Induced Gastric Cancer Cell Proliferation via Up-Regulation of Kruppel-Like Factor 4 through Down-Regulation of IGF-IR and AKT Phosphorylation

Dopamine, by Acting through Its D2 Receptor, Inhibits Insulin-Like Growth Factor-I... The overexpression of insulin-like growth factor receptor-I (IGF-IR) and the activation of its signaling pathways both play critical roles in the development and progression of gastric cancer. Dopamine (DA), a major enteric neurotransmitter, has been reported to have a wide variety of physiological functions in the gastrointestinal tract, including the stomach. We have previously reported that both DA and tyrosine hydroxylase, the rate-limiting enzyme required for the synthesis of DA, are lost in malignant gastric tissues. The effect of this loss of DA on IGF-IR-induced growth of gastric cancer has not yet been elucidated; we therefore investigated the role of DA, if any, on IGF-IR-induced proliferation of malignant gastric cells. There was a significant increase in the expression of phosphorylated IGF-IR and its downstream signaling molecule AKT in human malignant gastric tissues compared with normal nonmalignant tissues. Furthermore, to determine whether this loss of DA has any effect on the activation of IGF-IR signaling pathways in malignant gastric tumors, in vitro experiments were undertaken, using AGS gastric cancer cells. Our results demonstrated that DA acting through its D 2 receptor, inhibits IGF-I-induced proliferation of AGS cells by up-regulating KLF4, a negative regulator of the cell cycle through down regulation of IGF-IR and AKT phosphorylation. Our results suggest that DA is an important regulator of IGF-IR function in malignant gastric cancer cells. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png American Journal of Pathology American Society for Investigative Pathology

Dopamine, by Acting through Its D2 Receptor, Inhibits Insulin-Like Growth Factor-I (IGF-I)-Induced Gastric Cancer Cell Proliferation via Up-Regulation of Kruppel-Like Factor 4 through Down-Regulation of IGF-IR and AKT Phosphorylation

Dopamine, by Acting through Its D2 Receptor, Inhibits Insulin-Like Growth Factor-I (IGF-I)-Induced Gastric Cancer Cell Proliferation via Up-Regulation of Kruppel-Like Factor 4 through Down-Regulation of IGF-IR and AKT Phosphorylation

American Journal of Pathology , Volume 177 (6): 2701 – Dec 1, 2010

Abstract

The overexpression of insulin-like growth factor receptor-I (IGF-IR) and the activation of its signaling pathways both play critical roles in the development and progression of gastric cancer. Dopamine (DA), a major enteric neurotransmitter, has been reported to have a wide variety of physiological functions in the gastrointestinal tract, including the stomach. We have previously reported that both DA and tyrosine hydroxylase, the rate-limiting enzyme required for the synthesis of DA, are lost in malignant gastric tissues. The effect of this loss of DA on IGF-IR-induced growth of gastric cancer has not yet been elucidated; we therefore investigated the role of DA, if any, on IGF-IR-induced proliferation of malignant gastric cells. There was a significant increase in the expression of phosphorylated IGF-IR and its downstream signaling molecule AKT in human malignant gastric tissues compared with normal nonmalignant tissues. Furthermore, to determine whether this loss of DA has any effect on the activation of IGF-IR signaling pathways in malignant gastric tumors, in vitro experiments were undertaken, using AGS gastric cancer cells. Our results demonstrated that DA acting through its D 2 receptor, inhibits IGF-I-induced proliferation of AGS cells by up-regulating KLF4, a negative regulator of the cell cycle through down regulation of IGF-IR and AKT phosphorylation. Our results suggest that DA is an important regulator of IGF-IR function in malignant gastric cancer cells.

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Publisher
American Society for Investigative Pathology
Copyright
Copyright © 2010 by the American Society for Investigative Pathology.
ISSN
0002-9440
eISSN
1525-2191
DOI
10.2353/ajpath.2010.100617
pmid
21075859
Publisher site
See Article on Publisher Site

Abstract

The overexpression of insulin-like growth factor receptor-I (IGF-IR) and the activation of its signaling pathways both play critical roles in the development and progression of gastric cancer. Dopamine (DA), a major enteric neurotransmitter, has been reported to have a wide variety of physiological functions in the gastrointestinal tract, including the stomach. We have previously reported that both DA and tyrosine hydroxylase, the rate-limiting enzyme required for the synthesis of DA, are lost in malignant gastric tissues. The effect of this loss of DA on IGF-IR-induced growth of gastric cancer has not yet been elucidated; we therefore investigated the role of DA, if any, on IGF-IR-induced proliferation of malignant gastric cells. There was a significant increase in the expression of phosphorylated IGF-IR and its downstream signaling molecule AKT in human malignant gastric tissues compared with normal nonmalignant tissues. Furthermore, to determine whether this loss of DA has any effect on the activation of IGF-IR signaling pathways in malignant gastric tumors, in vitro experiments were undertaken, using AGS gastric cancer cells. Our results demonstrated that DA acting through its D 2 receptor, inhibits IGF-I-induced proliferation of AGS cells by up-regulating KLF4, a negative regulator of the cell cycle through down regulation of IGF-IR and AKT phosphorylation. Our results suggest that DA is an important regulator of IGF-IR function in malignant gastric cancer cells.

Journal

American Journal of PathologyAmerican Society for Investigative Pathology

Published: Dec 1, 2010

References