ABSTRACT
Prostate cancer represents a major concern in human oncology and the phytoalexin resveratrol (RES) inhibits growth and proliferation of prostate cancer cells through the induction of apoptosis. In addition, previous data indicate that in oestrogen-responsive human breast cancer cells, RES induces apoptosis by inhibition of the phosphoinositide-3-kinase (PI3K) pathway. Here, using androgen receptor (AR)-positive LNCaP and oestrogen receptor alpha (ERalpha)-expressing PC-3 prostate tumour cells, we have analysed whether the antiproliferative activity of RES takes place by inhibition of the AR- or ERalpha-dependent PI3K pathway. Although RES treatment (up to 150 microM) decreased AR and ERalpha protein levels, it did not affect AR and ERalpha interaction with p85-PI3K. Immunoprecipitation and kinase assays showed that RES inhibited AR- and ERalpha-dependent PI3K activities in LNCaP and PC-3, respectively. Consistently, lower PI3K activities correlated with decreased phosphorylation of downstream targets protein kinase B/AKT (PKB/AKT) and glycogen synthase kinase-3 (GSK-3). GSK-3 dephosphorylation could be responsible for the decreased cyclin D1 levels observed in both cell lines. Importantly, RES markedly decreased PKB/AKT phosphorylation in primary cultures from human prostate tumours, suggesting that the mechanism proposed here could take place in vivo. Thus, RES could have antitumoral activity in androgen-sensitive and androgen-non-sensitive human prostate tumours by inhibiting survival pathways such as that mediated by PI3K.
Subject(s)
Phosphatidylinositol 3-Kinases/metabolism , Prostatic Neoplasms/metabolism , Protein Processing, Post-Translational/drug effects , Receptors, Androgen/metabolism , Receptors, Estrogen/metabolism , Stilbenes/pharmacology , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Glycogen Synthase Kinase 3/metabolism , Humans , Male , Models, Biological , Phosphorylation/drug effects , Prostatic Neoplasms/pathology , Protein Binding/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Resveratrol , Signal Transduction/drug effects , Tumor Cells, CulturedABSTRACT
The main objective of this study was to evaluate the influence of the products secreted by the human embryo upon the three subtypes of beta-AR (beta1, beta2, beta3). Cell cultures were developed using endometrial biopsies, taken on day 7 after ovulation, from four healthy women <35 years of age, with regular cycles and infertility due only to male factors. Embryos from women with a normal uterine cavity and endometrial lining were incubated until they reached the 4-cell stage, before being transferred to their mother's uterus. Culture media for embryo incubation were derived from two groups: (i) embryos that achieved pregnancy, (ii) embryos which failed to implant. Control and experimental endometrial cell culture plates were treated with the two embryo culture media, with or without 10(-9) mol/l oestradiol and 10(-7) mol/l progesterone for 48 h. Expression of the three subtypes of beta-AR was assessed by RT-PCR. Beta1-AR was expressed in both control and experimental plates; beta2-AR was expressed only in plates incubated with embryonic culture media of embryos which achieved pregnancy, in both hormonal conditions, with or without oestradiol and progesterone. Beta3-AR was not expressed in any condition. Thus secretory products of human embryos may influence gene expression of beta2-AR concentrations in the human endometrium, and this subtype of beta-AR may be involved in implantation.