Vav3, a Rho GTPase Guanine Nucleotide Exchange Factor, Increases during Progression to Androgen Independence in Prostate Cancer Cells and Potentiates Androgen Receptor Transcriptional Activity

Abstract

The progression of prostate cancer from androgen dependence to androgen independence is often accompanied by enhanced androgen receptor (AR) transcriptional activity. We observed a marked increase in the expression of Vav3, a Rho GTPase guanine nucleotide exchange factor (GEF), during the progression of human prostate cancer LNCaP cells to the androgen-independent derivative, LNCaP-R1. GEFs activate Rho family GTPases by promoting the exchange of GDP for GTP. Reporter gene assays showed that Vav3 potentiated AR transcriptional activity, and knock down of Vav3 resulted in decreased AR transactivation. Vav3 also increased androgen-induced levels of prostate-specific antigen mRNA. Furthermore, Vav3 enhanced AR activity at subnanomolar concentrations of androgen. This finding is particularly relevant because low androgen levels may be present in prostate tissue of patients undergoing androgen deprivation therapy. Enhancement of AR activity by Vav3 required amino terminal activation function 1 (AF1) of AR; however, Vav3 did not interact with AR or increase AR levels. Neither GEF function nor the C-terminal domains of Vav3 were required for Vav3-mediated enhancement of AR activity; however, the pleckstrin homology domain was obligatory. These data show that Vav3 levels rise during progression to androgen independence and support continued AR signaling (even under conditions of low androgen) by a novel GEF-independent cross-talk mechanism.

Novel Interaction between the Co-chaperone Cdc37 and Rho GTPase Exchange Factor Vav3 Promotes Androgen Receptor Activity and Prostate Cancer Growth*

“…9, D and E). This finding is consistent with our demonstration that Vav3 GEF activity is not required for Vav3 co-activation of AR in the presence of hormone (4).…”

“…Targeting a constitutively active Vav3 allele to prostate epithelium of transgenic mice results in prostate adenocarcinoma development (10). Consistent with a key role in CRPC, Vav3 enhances AR transcriptional activity and confers robust castration-resistant growth in a tumor xenograft model (4,11).…”

“…Thus, Rho GTPase interaction with Vav3 is unlikely to be involved in Vav3 co-activation of AR. Other binding proteins such as EGF receptor, insulin receptor, and insulin-like growth factor receptor interact with the C-terminal SH3-SH2-SH3 domains of Vav3, which are also dispensable for AR co-activation (4). In this study, we sought to identify proteins that interact with Vav3 and may play a role in AR co-activation.…”

“…The androgen receptor (AR) 4 has a critical role in prostate cancer development, growth, and progression. Androgen deprivation therapy is typically implemented in advanced prostate cancer and effectively halts tumor growth; however, this response is temporary.…”

ROCK Mediates Phorbol Ester-induced Apoptosis in Prostate Cancer Cells via p21Cip1 Up-regulation and JNK

“…Although there is very limited information regarding the expression and regulation of Rho-GEFs in prostate cancer cells, it is conceivable that mechanisms such as those described above and/or alternative yet unknown mechanisms may operate in prostate cancer cells, which requires further investigation, since they should provide relevant information on how PKC␦ modulates RhoA in the context of apoptotic responses. Candidate Rho GEFs include Vav3, which has been implicated in prostate cancer progression (42), as well as LARG and PDZ-Rho-GEF, which mediate downstream Rho signaling in prostate cancer models (43,44).…”