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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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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DOI: https://doi.org/10.1038/sj.onc.1210316
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