ed the anti cancer potential method of interrupting the Vav3 Inhibitors,Modulators,Libraries signal ing pathway using siRNA followed by investigating the impact of si Vav3 in combination with doceta el. The goals of this study were to e plore Vav3 as a novel therapeutic target for human prostate cancer, define the biological effects of si Vav3 when combined with doceta el in human prostate cancer cells in culture and e perimental animal models, and characterize the downstream signaling pathways of Vav3 in human pros tate cancer cells. This approach allowed us to advance our understanding of the possible importance of Vav3 as an efficacious therapeutic modality for prostate cancer beyond its commonly described associations with cell morphology and transformation. In the present study, we made certain observations.

Inhibitors,Modulators,Libraries Vav3 was overe pressed in LNCaP cells cultured under chronic hypo ia characterizing androgen inde pendence. Inhibitors,Modulators,Libraries Vav3 activated pro survival signaling pathways, including the activation Inhibitors,Modulators,Libraries of PI3K Akt and ERK, which caused downstream Bad and AR phosphorylation in LNCaPH cells. Downregulation of Vav3 signaling pathways by siRNA in combination with doceta el signifi cantly inhibited LNCaPH cell growth through the induction of apoptosis in vitro and in mouse enografts in vivo. si Vav3 inhibited the phosphorylation of Akt and ERK, resulting in the inhibition of Bad and AR phos phorylation. Doceta el also inhibited the phosphoryl ation of Akt and ERK but activated JNK, resulting in increased Bcl 2 phosphorylation, and decreased Bad phos phorylation.

To the best of our knowledge, this is the first report to show that siRNA knockdown of Vav3 can be combined with doceta el against prostate cancer to GSK-3 yield increased sensitivity in vitro and in vivo. Recent studies have suggested controversies in the roles of hypo ic tumor microenvironment in prostate cancer. Dihydrotestosterone increased hypo ia response element mediated transcriptional activity in pros tate cancer, and androgen is involved in the response to hypo ia through hypo ia inducible factor 1. In addition, castration therapy was reported to decrease the synthesis of vascular growth factors, such as VEGF and angiopoietins, and upregulate hypo ia, leading to apop tosis in prostate cancer. Therefore, androgen deprivation therapy, which induces apoptosis by degen erating the vascular support system of the tumor, is rea sonable for androgen dependent prostate cancer.

In contrast, tumor hypo ia is progressively associated with increased AR activity, reduced o idative defense, gen omic instability, and apoptosis resistance, and it may be associated with the transition to androgen independence in prostate cancer. Suzuki et al. reported that prostate inhibitor Y-27632 cancer progresses in hypo ic conditions and transforms to the androgen independent state by suppress ing the androgen response. Moreover, Butterworth et al. also demonstrated that hypo ia could select for an drogen independent prostate cancer cells with more malig nant behaviors including invasio