Differential Roles of Carboxylated and Uncarboxylated Osteocalcin in Prostate Cancer Growth

Abstract

Serum levels of osteocalcin (OC), a bone matrix non-collagenous protein secreted by osteoblasts, are correlated with pathological bone remodeling such as the bone metastasis of cancer, as well as physiological bone turnover. The pathological roles in prostate cancer growth of the two existing types of serum OC, γ-carboxylated (GlaOC) and lower- (or un-) carboxylated (GluOC), have not yet been discriminatively examined. In the present study, we demonstrate that normal prostate epithelial cell growth was promoted by both types of OC, while growth of cancer cells in the prostate was accelerated by GlaOC but suppressed by GluOC. We suggest that OC regulates prostate cancer growth depending on the γ-carboxylation, in part by triggering reduced phosphorylation of receptor tyrosine kinases.

Keywords: osteocalcin; prostate cancer.

Figure 1

Effects of GlaOC and GluOC on human prostate cell growth. Effect of GlaOC (A) and GluOC (B) on PC-3, PPC-1, and ProEpi cells. Each assay was performed in triplicate. Left and right panels represent WST-8 (cell viability) assays at 24 h and 48 h and BrdU uptake (DNA synthesis) assays at 24 h, respectively. The data represent mean ± SD from three experiments. Mean data are expressed as a ratio of the control. *P < 0.05 and **P < 0.01 versus the corresponding value for cells treated with vehicle.

Figure 2

Phospho-RTKs array in PPC-1 (A) and ProEpi (B) cells. Quantitation of the dot densities of phospho-RTKs was performed using scanning images and ImageQuant LAS 4000 software (GE Healthcare UK, Buckinghamshire, England). Each pair of the kinase dots that increased (red) or decreased (blue) compared with the controls is enclosed in a square. Each assay was repeated three times. Four separate results are summarized in the graphs. *P < 0.05 versus the corresponding value for the control.

Figure 2

Phospho-RTKs array in PPC-1 (A) and ProEpi (B) cells. Quantitation of the dot densities of phospho-RTKs was performed using scanning images and ImageQuant LAS 4000 software (GE Healthcare UK, Buckinghamshire, England). Each pair of the kinase dots that increased (red) or decreased (blue) compared with the controls is enclosed in a square. Each assay was repeated three times. Four separate results are summarized in the graphs. *P < 0.05 versus the corresponding value for the control.