A glycolytic mechanism regulating an angiogenic switch in prostate cancer.
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.
Wang
Jianhua
J
Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, 1011 North University Avenue, Ann Arbor, MI 48109, USA.
Wang
Jincheng
J
Dai
Jinlu
J
Jung
Younghun
Y
Wei
Chuen-Long
CL
Wang
Yu
Y
Havens
Aaron M
AM
Hogg
Phillip J
PJ
Keller
Evan T
ET
Pienta
Kenneth J
KJ
Nor
Jacques E
JE
Wang
Cun-Yu
CY
Taichman
Russell S
RS
D043168:Angiostatins / Q000096:biosynthesis; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis / Q000378:metabolism; D008297:Male; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D010735:Phosphoglycerate Kinase / Q000096:biosynthesis* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000098:blood supply* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000378:metabolism
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D016209:Interleukin-8; D019718:Receptors, CXCR4; D042461:Vascular Endothelial Growth Factor A; D043168:Angiostatins; D010735:Phosphoglycerate Kinase