In the past, molecular mechani

In the past, molecular mechanisms for the progression to the hormone refractory state have been proposed based on e perimental evidence. The androgen receptor dependent mechanisms include androgen independent activation of AR, AR overe pression or muta tions, which could allow AR to respond to lower levels of androgens or be directly activated by Inhibitors,Modulators,Libraries other ligands, increased e pression of steroidogenic enzymes, and indirect activation of AR by cell surface receptors such as HER2, the interleukin 6 receptor and G protein coupled receptors. The AR independent mechanisms include mutations of tumor suppressor genes, Inhibitors,Modulators,Libraries e pression of various oncogenes affecting cell growth and death, enhanced angiogenesis, bypassing the AR pathway, and prostate cancer stem cell regeneration. Recently, Lyons et al.

reported a novel ligand independent GSK-3 AR activation through Rho guanosine triphosphatase signaling in prostate cancer in vivo and in vitro. Inhibitors,Modulators,Libraries The levels of Vav3, a Rho GTPase guanine nucleotide e change factor, are elevated in human prostate cancer specimens, and they increase during the progression of prostate cancer to androgen independence by enhance ment of AR transcriptional activity. The Vav gene was first identified in hematopoietic cells with oncogenic activity. Since the discovery of the Vav oncogene, new family members have been identified in mammalian cells. The biochemical functions of Vav family proteins have been e tensively Inhibitors,Modulators,Libraries investigated. Vav1 e pression is restricted to hematopoietic cells, and it is involved in the formation of the immune synapse. Vav2 and Vav3 are more ubiquitously e pressed.

Vav proteins contain the Dbl homology domain, which confers GEF activity, as well as protein interaction domains that allow them to function in pathways regulating actin cytoskeleton organization. In particular, their GEF activity is the most important function among them. Vav3, a signal transducer of receptor protein tyrosine kinase, is involved in various cellular signaling processes including cell morphology modulation and cell transformation with oncogenic activity. In the current study, Vav3 was demonstrated to bind to phosphatidylinositol 3 kinase, leading to PI3K activation with cell transformation activity. In a previous report, Dong et al. found that Vav3 en hances AR activity partially through PI3K Akt signaling and stimulates androgen independent growth in prostate cancer. We further revealed that tumor cell hypo ia induced Vav3 overe pression with androgen independ ent growth and malignant behavior in LNCaP cells. Therefore, we hypothesized that Vav3 has an im portant role in regulating the growth and survival of prostate cancer cells under hypo ic conditions and that it is a novel therapeutic target for the treatment of HRPC.

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