RalA regulates vascular endothelial growth factor-C (VEGF-C) synthesis in prostate cancer cells during androgen ablation

F. Rinaldo, J. Li, E. Wang, M. Muders, K. Datta

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1731-1738
Number of pages8
JournalOncogene
Volume26
Issue number12
DOIs
StatePublished - Mar 15 2007

Keywords

  • Androgen
  • Prostate cancer
  • RalA
  • Reactive oxygen species
  • VEGF-C

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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