however, doceta el does not e hibit sufficient activity when ad ministered as a single agent. However, when doceta el is used in combination with other therapeutic modalities, this therapeutic strategy may provide mean ingful improvements in the management of HRPC. In this study, we report studies assessing in vitro and in vivo combinations of doceta el with small interfering Inhibitors,Modulators,Libraries RNA for Vav3. To the best of our knowledge, we have reported for the first time that interrupting the Vav3 signaling pathway using siRNA induces apoptosis and enhances doceta el sensitivity through the inhibition of PI3K Akt, e tracellu lar Inhibitors,Modulators,Libraries signal regulate kinase, and AR signaling a is in human prostate cancer.

Results E pression levels of Vav3 in parental and chronic hypo ic LNCaP cells The e pression of Vav3 was assessed by immunoblot ana lysis and immunocytochemistry in parental LNCaP cells and LNCaP cells cultured under hypo ic GSK-3 condi tions for over si months. Compared with LNCaP cells, LNCaPH cells and KPK13 cells as positive control e pressed higher levels of Vav3. Effects of si Vav3 and doceta el on Vav3 e pression and cell proliferation in LNCaPH cells Because Vav3 increased LNCaP cell growth in vitro and Vav3 overe pression was observed in LNCaPH cells e hibiting androgen independent behavior compared with its e pression in LNCaP cells, we tested the si Vav3 treatment resulted in the death of 0. 5% and 8% of cells respectively, whereas treatment with doceta el alone or si Vav3 plus doceta el resulted in the death of 48% and 78% of cells per field, respectively.

These results suggest that Vav3 depletion significantly sensitizes Inhibitors,Modulators,Libraries LNCaPH cells to doceta el treatment by indu cing cell death. Effects of si Vav3 and doceta el on the activation of Akt, ERK, and JNK signaling in LNCaPH cells To clarify the molecular mechanisms by which si Vav3 and doceta el promote the death of LNCaPH cells, we investigated the effects of si Vav3 and doceta el on the phosphorylation Inhibitors,Modulators,Libraries of Akt, ERK, and JNK. LNCaPH cells were treated with si Vav3, 5 nM doceta el, or si Vav3 plus 5 nM doceta el for 48 h. Treatment with si Vav3 led to the attenuation of Akt phosphorylation at Ser 473, a site required for Akt activation, and ERK phosphorylation at Thr 202 and Tyr 204, which are sites required for ERK activation, but no effect was observed on JNK phosphoryl ation.

Similarly, doceta el treatment attenu ated Akt and ERK phosphorylation and strongly induced JNK phosphorylation at Thr 183 and Tyr 185, which are sites required for JNK activation. When LNCaPH cells were treated with si Vav3 plus doceta el, Akt phosphorylation was completely abolished with the inhibition of ERK phosphorylation and JNK acti vation. Figure 2E summarizes the results of possibility that Vav3 induced intracellular signaling may be a therapeutic target for the treatment of HRPC. LNCaPH cells were transiently transfected with either si Vav3 or si Scr.