cAMP-responsive element-binding protein regulates vascular endothelial growth factor expression: implication in human prostate cancer bone metastasis.
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.
Wu
D
D
Molecular Urology and Therapeutics Program, Department of Urology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA. dwu2@emory.edu
Zhau
H E
HE
Huang
W-C
WC
Iqbal
S
S
Habib
F K
FK
Sartor
O
O
Cvitanovic
L
L
Marshall
F F
FF
Xu
Z
Z
Chung
L W K
LW
D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D017362:Cyclic AMP Response Element-Binding Protein / Q000032:analysis / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000235:genetics*
D017362:Cyclic AMP Response Element-Binding Protein; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A