Sex hormones induce direct epithelial and inflammation-mediated oxidative/nitrosative stress that favors prostatic carcinogenesis in the noble rat.
Oxidative and nitrosative stress have been implicated in prostate carcinogenesis, but the cause(s) of redox imbalance in the gland remains poorly defined. We and others have reported that administration of testosterone plus 17beta-estradiol to Noble rats for 16 weeks induces dysplasia and stromal inflammation of the lateral prostate (LP) but not the ventral prostate. Here, using laser capture microdissected specimens, we found that the combined hormone regimen increased the expression of mRNA of specific members of NAD(P)H oxidase (NOX-1, NOX-2, and NOX4), nitric-oxide synthase [NOS; inducible NOS and endothelial NOS], and cyclooxygenase (COX-2) in the LP epithelium and/or its adjacent inflammatory stroma. Accompanying these changes was the accumulation of 8-hydroxy-2'-deoxyguanosine, 4-hydroxynonenal protein adducts, and nitrotyrosine, primarily in the LP epithelium, suggesting that NOX, NOS, and COX may mediate hormone-induced oxidative/nitrosative stress in epithelium. We concluded that the oxidative/nitrosative damage resulting from the testosterone-plus-17beta-estradiol treatment is not solely derived from stromal inflammatory lesions but likely also originates from the epithelium per se. In this context, the up-regulation of COX-2 from epithelium represents a potential mechanism by which the hormone-initiated epithelium might induce inflammatory responses. Thus, we link alterations in the hormonal milieu with oxidative/nitrosative/inflammatory damage to the prostate epithelium that promotes carcinogenesis.
Tam
Neville N C
NN
Department of Environmental Health, Kettering Complex, Room 130, 3223 Eden Ave., University of Cincinnati Medical Center, PO Box 670056, Cincinnati, OH 45267-0056, USA.
Leav
Irwin
I
Ho
Shuk-Mei
SM
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000032:analysis; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology; D004958:Estradiol / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity; D012739:Gonadal Steroid Hormones / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity; D007834:Lasers; D008297:Male; D042282:Microdissection; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011467:Prostate; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013739:Testosterone / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity
D012739:Gonadal Steroid Hormones; D012333:RNA, Messenger; D013739:Testosterone; D004958:Estradiol; D000080242:8-Hydroxy-2'-Deoxyguanosine; D019001:Nitric Oxide Synthase; D051546:Cyclooxygenase 2; D009247:NADH, NADPH Oxidoreductases; D003849:Deoxyguanosine
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