Increased ErbB-2 tyrosine kinase activity, MAPK phosphorylation, and cell proliferation in the prostate cancer cell line LNCaP following treatment byselect 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 overexpre ssion of erbB-2 occurs in many forms of cancer, such as of the breast, colo n, and prostate, and is an indicator of poor prognosis in those diseases. I n the human prostate cancer cell lines LNCaP and PC-3, erbB-2 kinase was ac tivated by pesticides of different chemical classes: (1) the organochlorine insecticides beta -hexa-chlorocyclohexane (beta -HCH), o,p'-dichlorodiphen yltrichloroethane (o,p'-DDT), and heptachlor epoxide; (2) the pyrethroid in secticide 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 pr oliferative 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 andro gen receptor antagonist p,p'-dichlorodiphenyldichloroethene (p,p'-DDE), ind icating that this effect of o,p'-DDT does not occur through direct interact ion with the androgen receptor. Together these data demonstrate a putative mechanism for the action of certain pesticides in hormonal carcinogenesis.