We noted that inhibition of survival kinase cascades targeting Bad, in cluding the inhibition of Akt and ERK phosphorylation by si Vav3, resulted in apoptosis. In addition, si Vav3 simultaneously inhibited the androgen signaling mediated by AR, a ligand activated transcrip tion factor and survival factor. It has been amply docu mented that AR, PI3K Akt, and ERK pathways are important features contributing to uncontrolled prostate cancer cell growth and survival. In addition, increased AR activity is caused by crosstalk between AR and mul tiple intracellular signaling cascades, particularly PI3K Akt and ERK pathways. Inhibitors,Modulators,Libraries Consistent with a previ ous report, Vav3 downregulation inhibited AR phosphor ylation through its convergent signaling Inhibitors,Modulators,Libraries network of PI3K Akt and ERK in LNCaPH cells.

Because PI3K Akt and ERK pathways can regulate prostate cancer survival through the AR pathway, we investigated whether inhibiting PI3K Akt and ERK pathways by kinase specific inhibitors could affect AR phosphorylation. We found that treatment with LY294002 or U0126 decreased the phos phorylation of AR with a concomitant reduction of Akt and ERK phosphorylation Drug_discovery in both LNCaP and LNCaPH cells. Thus, treatment with LY294002 increased apoptosis, whereas the effect of U0126 on cell apoptosis was attenuated compared with that of LY294002 because of the low level of basal ERK activity. Interestingly, the ef fects of LY294002 on apoptosis was stronger in LNCaPH cells than in LNCaP cells because of the high basal Akt phosphorylation level.

Collectively, these results indicate that the PI3K Akt signaling pathway plays a crucial role in LNCaPH cell growth, although cancer cell growth regu lated by Vav3, at least in part, originated from activated ERK signaling. Our observations support the view that the PI3K Akt pathway, which is activated by Vav3, is mainly involved in AR activity in prostate cancer development Inhibitors,Modulators,Libraries and progression. In this study, although doceta el also induced LNCaPH cell apoptosis by the inhibition of Bad phosphorylation in cluding the inhibition of Akt and ERK phosphorylation, the level of AR phosphorylation was unaffected by doceta el. It has been reported that doceta el can Inhibitors,Modulators,Libraries induce apoptosis by PI3K Akt inhibition in prostate cancer. Similarly, our findings suggested that Bad phosphorylation is mainly regulated by the PI3K Akt pathway because basal ERK activity is very low in LNCaPH cells, although ERK phosphorylation is inhibited by doceta el. JNK, also called SAPK, is involved in development, morphogenesis, cell differentiation, and cell death in re sponse to various environmental stresses including mito gen growth factors, inflammatory cytokines, o idative stress, and diverse e tracellular stimuli including cyto to ic drugs.