Androgen-induced PSA expression requires not only activation of AR but also endogenous IGF-I or IGF-I/PI3K/Akt signaling in human prostate cancer epithelial cells.
Prostate cancer (PrCa) risk is positively associated with levels of insulin-like growth factor I (IGF-I) and prostate specific antigen (PSA), both androgen receptor (AR) signaling target genes in PrCa cells. Although activated AR is required for androgen-induction of expression of both genes, effects of the IGF-I signaling pathways on the ... androgen-induction of PSA have not been studied.Human prostate stromal and epithelial cancer cells were treated alone or in coculture with steroid hormone and/or inhibitors. Gene or protein expression was analyzed by real time RT-PCR or Western blotting of lysates, nuclear extracts, or immunoprecipitated products.In PrCa epithelial cells, endogenous IGF-I, significantly induced by R1881, was required for R1881-induction of PSA. Increased IGF-I correlated with accumulation of cytoplasmic dephospho ?-catenin (CPDP ?-catenin), a co-activator of AR signaling. Exogenous IGF-I enhanced R1881-induced PSA and accumulation of CPDP ?-catenin in LAPC-4 cells. Functional depletion of IGF-I or IGF-I receptor diminished PSA induction. Induction of IGF-I reached a plateau while PSA consecutively increased. Inhibiting PI3K abolished R1881-induced Akt phosphorylation, CPDP and nuclear ?-catenin and nuclear association of AR/?-catenin, consequently abrogating R1881-induced expression of IGF-I and/or PSA.By integrating androgen, IGF-I and ?-catenin signaling pathways, these data reveal that androgen-induced PSA expression requires activation of AR and endogenous IGF-I or IGF-I/PI3K/Akt signaling, suggesting a positive feedback cycle for increased production of PSA associated with PrCa.
Mesh Terms:
Adenocarcinoma, Biomarkers, Tumor, Cell Line, Tumor, Epithelial Cells, Humans, Insulin-Like Growth Factor I, Male, Metribolone, Neoplasm Proteins, Oncogene Protein v-akt, Phosphatidylinositol 3-Kinases, Prostate, Prostate-Specific Antigen, Prostatic Neoplasms, Receptors, Androgen, Signal Transduction, beta Catenin
Adenocarcinoma, Biomarkers, Tumor, Cell Line, Tumor, Epithelial Cells, Humans, Insulin-Like Growth Factor I, Male, Metribolone, Neoplasm Proteins, Oncogene Protein v-akt, Phosphatidylinositol 3-Kinases, Prostate, Prostate-Specific Antigen, Prostatic Neoplasms, Receptors, Androgen, Signal Transduction, beta Catenin
Prostate
Date: May. 15, 2011
PubMed ID: 21031436
View in: Pubmed Google Scholar
Download Curated Data For This Publication
252930
Switch View:
- Interactions 1