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

Oncogene volume 26, pages 1731–1738 (2007)Cite this article

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.

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Acknowledgements

We thank Dr Donald Tindall and Dr Debabrata Mukhopadhyay for their helpful discussion. This work was partly supported by a Career Development project in prostate SPORE grant (Mayo Clinic) (1 PSOCA91956-3) and a New Investigator award grant from US Army Medical Research and Material Command (2B1636) of KD.

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  1. F Rinaldo and J Li: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology and Mayo Clinic Cancer Center, Mayo Clinic Foundation, Rochester, MN, USA

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

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  1. F Rinaldo
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Correspondence to K Datta.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Rinaldo, F., Li, J., Wang, E. et al. RalA regulates vascular endothelial growth factor-C (VEGF-C) synthesis in prostate cancer cells during androgen ablation. Oncogene 26, 1731–1738 (2007). https://doi.org/10.1038/sj.onc.1209971

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