title: Dopamine, by acting through its D2 receptor, inhibits insulin-like growth factor-I (IGF-I)-induced gastric cancer cell proliferation via up-regulation of Krüppel-like factor 4 through down-regulation of IGF-IR and AKT phosphorylation.
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.
authors.affiliation: Signal Transduction and Biogenic Amines Department, Chittaranjan National Cancer Institute, 37 S.P. Mukherjee Road, Kolkata 700026, India.
authors.forename: Subhalakshmi
authors.initials: S
authors.lastname: Ganguly
authors.forename: Biswarup
authors.initials: B
authors.lastname: Basu
authors.forename: Saurav
authors.initials: S
authors.lastname: Shome
authors.forename: Tushar
authors.initials: T
authors.lastname: Jadhav
authors.forename: Sudipta
authors.initials: S
authors.lastname: Roy
authors.forename: Jahar
authors.initials: J
authors.lastname: Majumdar
authors.forename: Partha Sarathi
authors.initials: PS
authors.lastname: Dasgupta
authors.forename: Sujit
authors.initials: S
authors.lastname: Basu
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000328:Adult; D000368:Aged; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000009:adverse effects / Q000494:pharmacology*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D017448:Receptors, Dopamine D2; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D004298:Dopamine