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cAMP-responsive element-binding protein regulates vascular endothelial growth factor expression: implication in human prostate cancer bone metastasis

Oncogene volume 26, pages 5070–5077 (2007)Cite this article

Abstract

Aberrant expression of vascular endothelial growth factor (VEGF) is associated with human prostate cancer (PCa) metastasis and poor clinical outcome. We found that both phosphorylation of cyclic AMP-responsive element-binding protein (CREB) and VEGF levels were significantly elevated in patient bone metastatic PCa specimens. A PCa ARCaP progression model demonstrating epithelial-to-mesenchymal transition exhibited increased CREB phosphorylation and VEGF expression as ARCaP cells became progressively more mesenchymal and bone-metastatic. Activation of CREB induced, whereas inhibition of CREB blocked, VEGF expression in ARCaP cells. CREB may regulate VEGF transcription via a hypoxia-inducible factor-dependent mechanism in normoxic conditions. Activation of CREB signaling is involved in the coordinated regulation of VEGF and may pre-dispose to PCa bone metastasis.

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Abbreviations

ATF:

activating transcription factor

cAMP:

cyclic AMP

CBP:

CREB-binding protein

ChIP:

chromatin immunoprecipitation

CM:

conditioned medium

CRE:

cAMP-responsive element

CREB:

CRE-binding protein

ELISA:

enzyme-linked immunosorbent assay

EMT:

epithelial-to-mesenchymal transition

FSK:

forskolin

IHC:

immunohistochemistry

HIF:

hypoxia-inducible factor

HRE:

hypoxia-response element

PCa:

prostate cancer

p-CREB:

phosphorylated CREB

PKA:

protein kinase A

RT–PCR:

reverse-transcription–PCR

siRNA:

small interfering RNA

VEGF:

vascular endothelial growth factor

VEGFR:

VEGF receptor

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Acknowledgements

We acknowledge editorial assistance from Gary Mawyer. This work was supported by grants from the NIH to LWKC (1P01 CA098912, PC040260, 1R01 CA108468, 5P20GM072069), and from the DoD to DW (PC060566).

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Authors and Affiliations

  1. Department of Urology and Winship Cancer Institute, Molecular Urology and Therapeutics Program, Emory University School of Medicine, Atlanta, GA, USA

    D Wu, H E Zhau, W-C Huang, S Iqbal, F F Marshall, Z Xu & L W K Chung

  2. Division of Oncology, Prostate Research Group, School of Molecular and Clinical Medicine, Western General Hospital, Edinburgh, UK

    F K Habib

  3. Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    O Sartor

  4. The Stanley Scott Cancer Center at LSU Health Sciences Center, New Orleans, LA, USA

    L Cvitanovic

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  1. D Wu
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Correspondence to D Wu or L W K Chung.

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

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Wu, D., Zhau, H., Huang, WC. et al. cAMP-responsive element-binding protein regulates vascular endothelial growth factor expression: implication in human prostate cancer bone metastasis. Oncogene 26, 5070–5077 (2007). https://doi.org/10.1038/sj.onc.1210316

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