Prostate carcinomas frequently express estrogen receptors(ER), irrespective of androgen receptor (AR) expression;however, the role of ERs and estrogens in prostate cancer iscontroversial. We found that 17B-estradiol (E2) is able tomarkedly up-regulate insulin-like growth factor (IGF)-Ireceptor (IGF-IR) mRNA and protein expression in both ARpositive(LNCaP cells) and AR-negative (PC-3 cells) prostatecancer cells. This effect occurs not only via ERA but also viaERB stimulation and is specific for IGF-IR because it does notinvolve the cognate insulin receptor. IGF-IR up-regulation isassociated with increased IGF-IR phosphorylation and withincreased mitogenic and motogenic activities in response toIGF-I. IGF-IR up-regulation by E2 does not require ER bindingto DNA and is poorly sensitive to antiestrogen blockade,whereas it is associated with the activation of cytosolic kinasecascades involving Src, extracellular signal–regulated kinase(ERK)-1/2, and, to a lesser extent, phosphatidylinositol 3-kinase and is sensitive to the inhibition of these kinases. Inconclusion, our data indicate that estrogens may contribute toIGF system deregulation in prostate cancer through theactivation of a nongenotropic pathway. Estrogens may havea role, therefore, in tumor progression to androgen independence.Inhibition of the IGF-IR or the Src-ERK pathway shouldbe considered, therefore, as an adjuvant therapy in prostatecancer.

17beta-estradiol up-regulates the insulin-like growth factor receptor through a nongenotropic pathway in prostate cancer cells

FRASCA, FRANCESCO;SQUATRITO, Sebastiano;BELFIORE A.
2007

Abstract

Prostate carcinomas frequently express estrogen receptors(ER), irrespective of androgen receptor (AR) expression;however, the role of ERs and estrogens in prostate cancer iscontroversial. We found that 17B-estradiol (E2) is able tomarkedly up-regulate insulin-like growth factor (IGF)-Ireceptor (IGF-IR) mRNA and protein expression in both ARpositive(LNCaP cells) and AR-negative (PC-3 cells) prostatecancer cells. This effect occurs not only via ERA but also viaERB stimulation and is specific for IGF-IR because it does notinvolve the cognate insulin receptor. IGF-IR up-regulation isassociated with increased IGF-IR phosphorylation and withincreased mitogenic and motogenic activities in response toIGF-I. IGF-IR up-regulation by E2 does not require ER bindingto DNA and is poorly sensitive to antiestrogen blockade,whereas it is associated with the activation of cytosolic kinasecascades involving Src, extracellular signal–regulated kinase(ERK)-1/2, and, to a lesser extent, phosphatidylinositol 3-kinase and is sensitive to the inhibition of these kinases. Inconclusion, our data indicate that estrogens may contribute toIGF system deregulation in prostate cancer through theactivation of a nongenotropic pathway. Estrogens may havea role, therefore, in tumor progression to androgen independence.Inhibition of the IGF-IR or the Src-ERK pathway shouldbe considered, therefore, as an adjuvant therapy in prostatecancer.
Insulin/growth factor; prostate cancer; role of 17-beta estradiol
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/20.500.11769/26852
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