Search

Prostate cancer mortality is primarily due to failure to cure patients with metastatic disease. In its early stages, prostate cancer growth is enhanced by androgens. As such, the primary therapy for advanced (locally extensive or metastatic) prostate cancer consists of androgen deprivation therapy by pharmacotherapeutic or surgical means. Eventually, the tumor recurs owing to a transition from androgen-dependence to a highly metastatic and androgen refractory (androgen depletion-independent) phenotype. As the detailed molecular mechanism underlying this transition to a more aggressive phenotype is poorly understood, it has been difficult to develop effective treatments for this advanced stage of the disease. We have previously reported an increase in vascular endothelial growth factor-C (VEGF-C) expression in human prostate cancer cells after androgen withdrawal. We have also shown increased expression of the androgen receptor co-activator BAG-1L by VEGF-C, suggesting the involvement of this growth factor in transactivation of the androgen receptor, even at low concentrations of androgen. In our present study, we show that androgen deprivation of human prostate carcinoma cells activates the small GTPase, RalA, a molecule important for human oncogenesis. RalA activation leads to VEGF-C upregulation. We also show that elevated levels of intracellular reactive oxygen species in prostate cancer cells under androgen-ablated conditions is the major inducer of RalA activation and VEGF-C synthesis.

Androgen ablation therapy is eventually followed by a more metastatic and androgen-refractory stage of prostate cancer. The detailed molecular mechanism of this gradual transition is not clearly understood. Recent reports correlate the high abundance of vascular endothelial growth factor-C (VEGF-C) to the lymph node metastasis seen in human prostate cancer (Tsurusaki et al., 1999). In this study, we report that androgen ablation in LNCaP cells augment the transcriptional upregulation of VEGF-C and the downregulation of the IGF-IR pathway, due to androgen withdrawal, is a potential mechanism for this observed VEGF-C transcription. Forkhead transcription factor FOXO-1, activated by SIRT-1, was identified as the downstream molecule within this pathway. Furthermore, the VEGF-C-induced increase of Bag-IL expression in LNCaP cells suggests that VEGF-C plays a role in the androgen-independent reactivation of the androgen receptor, resulting in androgen-refractory prostate cancer growth.