RalA regulates vascular endothelial growth factor-C (VEGF-C) synthesis in prostate cancer cells during androgen ablation.
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.
Rinaldo
F
F
Department of Biochemistry and Molecular Biology and Mayo Clinic Cancer Center, Mayo Clinic Foundation, Rochester, MN 55905, USA.
Li
J
J
Wang
E
E
Muders
M
M
Datta
K
K
D000728:Androgens / Q000172:deficiency*; D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D006801:Humans; D008297:Male; D016133:Polymerase Chain Reaction; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D042582:Vascular Endothelial Growth Factor C / Q000096:biosynthesis*; D020725:ral GTP-Binding Proteins / Q000502:physiology*
D000728:Androgens; D017931:DNA Primers; D017382:Reactive Oxygen Species; D042582:Vascular Endothelial Growth Factor C; C492198:RALA protein, human; D020725:ral GTP-Binding Proteins