Increased ErbB-2 tyrosine kinase activity, MAPK phosphorylation, and cell proliferation in the prostate cancer cell line LNCaP following treatment by select pesticides.
The oncogene erbB-2 codes for a receptor tyrosine kinase that functions as a key mitotic signal in a variety of cell types. Amplification or overexpression of erbB-2 occurs in many forms of cancer, such as of the breast, colon, and prostate, and is an indicator of poor prognosis in those diseases. In the human prostate cancer cell lines LNCaP and PC-3, erbB-2 kinase was activated by pesticides of different chemical classes: (1) the organochlorine insecticides beta-hexa-chlorocyclohexane (beta-HCH), o,p'-dichlorodiphenyltrichloroethane (o,p'-DDT), and heptachlor epoxide; (2) the pyrethroid insecticide trans-permethrin, and (3) the fungicide chlorothalonil. o,p'-DDT also causes phosphorylation of mitogen-activated protein kinase (MAPK) and cellular proliferation of the androgen-dependent LNCaP line. However, no proliferative effect was observed in the androgen-independent PC-3 line. The proliferative effect of o,p'-DDT in LNCaP could not be blocked by the androgen receptor antagonist p,p'-dichlorodiphenyldichloroethene (p,p'-DDE), indicating that this effect of o,p'-DDT does not occur through direct interaction with the androgen receptor. Together these data demonstrate a putative mechanism for the action of certain pesticides in hormonal carcinogenesis.
Department of Environmental Toxicology and the Center for Environmental Health Sciences, University of California, Davis, California 95616, USA. dmt@uic.edu
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D000230:Adenocarcinoma / Q000201:enzymology*; D000726:Androgen Antagonists / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D003633:Dichlorodiphenyl Dichloroethylene / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007306:Insecticides / Q000633:toxicity*; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000201:enzymology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D000726:Androgen Antagonists; D003633:Dichlorodiphenyl Dichloroethylene; D007306:Insecticides; D020929:Mitogen-Activated Protein Kinase Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases