Rapid xenograft tumor progression in beta-arrestin1 transgenic mice due to enhanced tumor angiogenesis.
beta-arrestins (beta-Arrs) are known to be associated with tumor signaling pathways such as transforming growth factor-beta1 (TGF-beta1), P53/Murine double minute (MDM2) and NF-kappaB. To investigate the role of beta-Arr in tumor progression in vivo, we generated beta-Arr transgenic mice by subcutaneously inoculating tumor cells in them. We found that the xenograft tumor initiated earlier and grew more rapidly in beta-Arr1 transgenic mice than in both the beta-Arr2 transgenic and wild-type mice after inoculating murine liver cancer Hepa1-6 cells or lymphoma EL4 cells. Moreover, matrix metalloproteinase 9 (MMP9) activity, vascular endothelial growth factor (VEGF) concentration in plasma and new small blood vessel formation in tumor tissues were enhanced in beta-Arr1 transgenic mice compared with those in control mice. In addition, injection of MMP9 inhibitors in beta-Arr1 transgenic mice abrogated all these effects and suppressed rapid tumor progression. Similar results were observed in human microvascular endothelial cells, where overexpressed beta-Arr1 did increase MMP9 activity and small blood vessel formation. Furthermore, phosphatidylinositol 3-kinase (PI3K) inhibitors could suppress beta-Arr1-enhanced MMP9 activity and the C-terminal 181-418 amino acids (aa) of beta-Arr1 was largely responsible for this effect. Our data reveal a functional role for beta-arrestin1 in tumor progression in vivo, in which overexpression of beta-Arr1 promotes MMP9 activity and tumor angiogenesis by providing a suitable microenvironment for tumor progression.
Zou
Lin
L
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Yang
Rongxi
R
Chai
Jingjing
J
Pei
Gang
G
D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D018450:Disease Progression; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
C000605253:ARRB1 protein, human; C000605254:ARRB2 protein, human; C000605255:Arrb1 protein, mouse; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D061965:Matrix Metalloproteinase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D019869:Phosphatidylinositol 3-Kinases; D020780:Matrix Metalloproteinase 9