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Upregulation of VEGF-C by androgen depletion: the involvement of IGF-IR-FOXO pathway

Oncogene volume 24, pages 5510–5520 (2005)Cite this article

Abstract

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.

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Acknowledgements

We thank Dr Donald Tindall and Dr Debabrata Mukhopadhyay for their helpful discussion and Julie Lau for helping us to write the manuscript. This work was partly supported by Career Development project in prostate spore grant (Mayo Clinic) (1 PSOCA91956-3) and New Investigator award grant from US Army Medical Research and material Command (2B1636) of KD.

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

    Jinping Li, Enfeng Wang, Francesca Rinaldo & Kaustubh Datta

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Correspondence to Kaustubh Datta.

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Li, J., Wang, E., Rinaldo, F. et al. Upregulation of VEGF-C by androgen depletion: the involvement of IGF-IR-FOXO pathway. Oncogene 24, 5510–5520 (2005). https://doi.org/10.1038/sj.onc.1208693

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