The cooked meat carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine activates the extracellular signal regulated kinase mitogen-activated protein kinase pathway.
During the cooking of meat, mutagenic and carcinogenic heterocyclic amines are formed, the most abundant of which, 2-amino-1-methyl-6-phenylimidazo[4-5-b]pyridine (PhIP), induces tumors of the prostate, colon, and mammary gland in rats. Humans consuming cooked meat are exposed to PhIP on a daily basis, yet few studies have assessed the effects of PhIP at dietary relevant concentrations. In addition to its genotoxic properties, recent studies have shown that PhIP can activate estrogen receptor-mediated signaling pathways at doses that are similar to those that may be present in the body following consumption of a cooked meat meal. In the present study, we examined whether such doses of PhIP can affect estrogen receptor-independent signal transduction via the mitogen-activated protein kinase (MAPK) extracellular signal-related kinase (ERK) pathway to influence proliferation and migration in the human mammary epithelial cell line MCF10A and the prostate cancer cell line PC-3. At doses shown to have a proliferative effect on MCF10A cells (10(-11)-10(-7) mol/L), PhIP induced a rapid, transient increase in phosphorylation of both MAPK/ERK kinase 1/2 and ERKs. Inhibition of this pathway significantly reduced the PhIP-induced proliferation of MCF10A cells and the migration of PC-3 cells. The data presented here show that levels of PhIP that approximate to human dietary exposure stimulate cellular signaling pathways and result in increased growth and migration, processes linked to the promotion and progression of neoplastic disease. These findings provide strong evidence that PhIP acts as a tumor initiator and promoter and that dietary exposure to this compound could contribute to carcinogenesis in humans.
Creton
Stuart K
SK
Biomolecular Medicine, Faculty of Medicine, Imperial College London, London, United Kingdom.
Zhu
Huijun
H
Gooderham
Nigel J
NJ
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D001940:Breast / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002273:Carcinogens / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002633:Chemotaxis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D015151:Immunoblotting; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D002273:Carcinogens; D007093:Imidazoles; D011960:Receptors, Estrogen; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases