Androgen receptor expression is regulated by the phosphoinositide 3-kinase/Akt pathway in normal and tumoral epithelial cells

Abstract

The androgen receptor (AR) is a ligand-responsive transcription factor known to play a central role in the pathogenesis of prostate cancer. However, the regulation of AR gene expression in the normal and pathological prostate remains poorly understood. This study focuses on the effect of the phosphoinositide 3-kinase (PI 3-kinase)/Akt axis on AR expression in vas deferens epithelial cells (VDEC), a suitable model to study androgen regulation of gene expression, and LNCaP cells (derived from a metastasis at the left supraclavicular lymph node from a 50-year-old patient with a confirmed diagnosis of metastatic prostate carcinoma). Taken together, our data show for the first time that the PI 3-kinase/Akt pathway is required for basal and dihydrotestosterone-induced AR protein expression in both VDEC and LNCaP. Inhibition of the PI 3-kinase/Akt pathway reduced AR expression and the decline in AR protein level correlated with a decrease in AR mRNA in VDEC but not in LNCaP. Since PI 3-kinase/Akt axis is active in prostate cancer, cross-talk between PI 3-kinase/Akt and AR signalling pathways may have implications for endocrine therapy.

APPL Suppresses Androgen Receptor Transactivation via Potentiating Akt Activity

“…Manin et al (38) show that LY294002 treatment could decrease AR protein and PSA mRNA levels but was unable to influence AR mRNA expression in LNCaP cells, whereas Sharma et al (39) find that LY294002 treatment did not suppress the AR protein level in LNCaP cells, but 4 h of LY294002 treatment decreased the PSA mRNA level, which is consistent with our report (Fig. 6B).…”

Retracted: Additive antitumor effects of the epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib (Iressa), and the nonsteroidal antiandrogen, bicalutamide (Casodex), in prostate cancer cells in vitro

“…Then, PKB/Akt, the key effector of the PI-3K, and AR may cooperate with each other to promote the PCa cell survival and growth as well as to regulate each other to maintain homeostasis of PCa cells. [32][33][34][35] Murillo et al 33 show that androgen ablation can increase PI-3K-Akt activity, implying that enhanced Akt activity may rescue cells from impairment of androgen withdrawal. Manin et al 34 show that LY294002 treatment could decrease AR protein and PSA levels in LNCaP cells, whereas Sharma et al 35 find that LY294002 treatment did not suppress the AR protein level in LNCaP cells, but 4 hr of LY294002 treatment decreased the PSA mRNA level.…”

Plasma membrane-associated sialidase (NEU3) regulates progression of prostate cancer to androgen-independent growth through modulation of androgen receptor signaling

“…To gain insights into the signaling pathway involved in the NEU3-mediated induction of these Sialidase regulates prostate cancer progression S Kawamura et al AR-related proteins, specific inhibitors of PI3K (LY294002) and MAPK (PD098059) pathways were used. 23 Treatment with LY294002 inhibited NEU3-induced EGR-1 and AR elevation, whereas PD098059 abolished the PSA increase ( Figure 4a). To be more convincing, the siRNAs for PI3K p110a and for MAPKK (MEK1/2) were separately used to block specifically these expressions.…”