Cyr61 is regulated by cAMP-dependent protein kinase with serum levels correlating with prostate cancer aggressiveness.
BACKGROUND
Cysteine-rich angiogenic inducer 61 (Cyr61) is an extracellular matrix protein involved in the transduction of growth factor and hormone signaling. Previously, we demonstrated that Cyr61 was highly expressed in prostate cancer (PCa) but that the expression levels were associated with a lower risk of PCa recurrence. In the present study, we demonstrate that serum Cyr61 is a potential biomarker that correlates with PCa aggressiveness. Furthermore, we also explore the potential mechanism underlying the changes in Cyr61 expression during PCa progression.


METHODS
Cyr61 concentrations in the medium from PCa cell lines and in serum samples obtained from PCa patients were measured by sandwich ELISA. Serum Cyr61 levels were correlated with disease characteristics and the association between Cyr61 expression changes by several types of stimulation or stress and cAMP/cAMP-dependent protein kinase (PKA) pathway were examined.


RESULTS
There was a positive correlation between Cyr61 levels in cell supernatants and mRNA expression in these cell lines. Serum Cyr61 levels were significantly higher in non-organ-confined PCa patients (116.3 ± 140.2 ng/ml) than in organ-confined PCa patients (79.7 ± 56.1 ng/ml) (P = 0.031). Cyr61 expression was up-regulated in response to both lysophosphatidic acid and androgen treatments which promoted PCa cell invasion. Serum starvation and phosphoinositide-3-kinase inhibition also resulted in Cyr61 up-regulation; however, they suppressed cell proliferation. Cyr61 up-regulation was correlated with an increase in cAMP and suppressed by PKA inhibition.


CONCLUSIONS
These findings suggest that Cyr61 expression in PCa is regulated by the cAMP/PKA pathway and that circulating Cyr61 levels are a potential serum-based biomarker for characterizing PCa.
Department of Urology, The James Buchanan Brady Urological Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Naoki
N
Terada
Takumi
T
Shiraishi
Yu
Y
Zeng
Steven M
SM
Mooney
David B
DB
Yeater
Leslie A
LA
Mangold
Alan W
AW
Partin
Prakash
P
Kulkarni
Robert H
RH
Getzenberg
D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood*; D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000097:blood / Q000502:physiology*; D055515:Cysteine-Rich Protein 61 / Q000097:blood*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000097:blood / Q000201:enzymology* / Q000473:pathology*
D014408:Biomarkers, Tumor; C501848:CCN1 protein, human; D055515:Cysteine-Rich Protein 61; D017868:Cyclic AMP-Dependent Protein Kinases