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Published on: March 15, 2016
RalA regulates vascular endothelial growth factor-C (VEGF-C) synthesis in prostate cancer cells during androgen
1Department of Biochemistry and Molecular Biology and Mayo Clinic Cancer Center, Mayo Clinic Foundation, Rochester, MN 55905, USA.
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.
Insights
Androgen deprivation therapy for prostate cancer can lead to a more aggressive tumor phenotype. Reactive oxygen species activate RalA, driving vascular endothelial growth factor-C (VEGF-C) synthesis and promoting cancer progression.
Area of Science:
- Oncology
- Molecular Biology
- Cellular Signaling
Background:
- Prostate cancer mortality is often linked to metastatic disease that becomes resistant to androgen deprivation therapy.
- The transition to an androgen-refractory, metastatic phenotype is poorly understood, hindering effective treatment development.
- Previous studies indicated increased vascular endothelial growth factor-C (VEGF-C) expression after androgen withdrawal.
Purpose of the Study:
- To investigate the molecular mechanisms underlying the transition of prostate cancer to an androgen-refractory state.
- To identify key signaling pathways activated by androgen deprivation in prostate cancer cells.
- To explore the role of reactive oxygen species in this transition.
Main Methods:
- Androgen deprivation was applied to human prostate carcinoma cells.
- Activation of the small GTPase RalA was assessed.
- Vascular endothelial growth factor-C (VEGF-C) expression levels were measured.
- Intracellular reactive oxygen species (ROS) levels were quantified.
Main Results:
- Androgen deprivation activated the small GTPase RalA in prostate carcinoma cells.
- RalA activation led to increased VEGF-C upregulation.
- Elevated intracellular reactive oxygen species (ROS) were identified as the primary inducer of RalA activation and subsequent VEGF-C synthesis under androgen-ablated conditions.
Conclusions:
- Androgen deprivation in prostate cancer cells triggers RalA activation, a key oncogenic molecule.
- This activation results in increased VEGF-C synthesis, potentially promoting metastasis.
- Reactive oxygen species play a critical role in mediating RalA activation and VEGF-C production during androgen ablation, offering potential therapeutic targets.
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