Abstract
The generation of an "angiogenic switch" is essential for tumor growth, yet its regulation is poorly understood. In this investigation, we explored the linkage between metastasis and angiogenesis through CXCL12/CXCR4 signaling. We found that CXCR4 regulates the expression and secretion of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1). Overexpression of PGK1 reduced the secretion of vascular endothelial growth factor and interleukin-8 and increased the generation of angiostatin. At metastatic sites, however, high levels of CXCL12 signaling through CXCR4 reduced PGK1 expression, releasing the angiogenic response for metastastic growth. These data suggest that PGK1 is a critical downstream target of the chemokine axis and an important regulator of an "angiogenic switch" that is essential for tumor and metastatic growth.
Highlights
1 expression, releasing the angiogenic response for metastastic growth. These data suggest that phosphoglycerate kinase 1 (PGK1) is a critical downstream target of the chemokine axis and an important regulator of an h ‘angiogenic switch’ that is essential for tumor and metastatic c growth. [Cancer Res 2007;67(1):149–59] r Introduction a Hypoxia is a central feature of many solid tumors, including prostate cancer, making them extremely resistant to chemotherapy
PGK1 is e regulated by hypoxia-inducible factor-1a (HIF-1a; ref. 5) and it is R often overexpressed in prostate cancer (6)
Overexpression of PGK1 increases the metastatic rate in vivo. most of the animals treated with either of the PC3 cells had Previously, we showed that antibody to CXCR4 blocked prostate cancer cell adhesion to endothelial cells and invasion into extradeveloped metastatic tumors
Summary
These determine if overexpression of CXCR4 directly regulates PGK1 expression, a HA-tagged vector containing the full-length cDNA of CXCR4 was used for transfection of the prostate cancer cell lines. Overexpression of CXCR4 resulted in down-regulation of PGK1 in the prostate cancer cell lines (Supplementary Fig. S2A). Overexpression of PGK1 increased the expression of CXCR4 in all of the prostate cancer cell lines (Fig. 1D, left).
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