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1. PLoS One. 2012;7(4):e35710. Epub 2012 Apr 24.

TIMP-2 Fusion Protein with Human Serum Albumin Potentiates
Anti-Angiogenesis-Mediated Inhibition of Tumor Growth by Suppressing MMP-2
Expression.

Lee MS, Jung JI, Kwon SH, Lee SM, Morita K, Her S.

Division of Bio-Imaging, Chuncheon Center, Korea Basic Science Institute,
Chuncheon, Republic of Korea.

TIMP-2 protein has been intensively studied as a promising anticancer candidate
agent, but the in vivo mechanism underlying its anticancer effect has not been
clearly elucidated by previous works. In this study, we investigated the
mechanism underlying the anti-tumor effects of a TIMP-2 fusion protein conjugated
with human serum albumin (HSA/TIMP-2). Systemic administration of HSA/TIMP-2
effectively inhibited tumor growth at a minimum effective dose of 60 mg/kg. The
suppressive effect of HSA/TIMP-2 was accompanied by a marked reduction of in vivo
vascularization. The anti-angiogenic activity of HSA/TIMP-2 was directly
confirmed by CAM assays. In HSA/TIMP-2-treated tumor tissues, MMP-2 expression
was profoundly decreased without a change in MT1-MMP expression of
PECAM-1-positive cells. MMP-2 mRNA was also decreased by HSA/TIMP-2 treatment of
human umbilical vein endothelial cells. Zymographic analysis showed that
HSA/TIMP-2 substantially decreased extracellular pro-MMP-2 activity (94-99%
reduction) and moderately decreased active MMP-2 activity (10-24% reduction),
suggesting MT1-MMP-independent MMP-2 modulation. Furthermore, HSA/TIMP-2 had no
effect on in vitro active MMP-2 activity and in vivo MMP-2 activity. These
studies show that HSA/TIMP-2 potentiates anti-angiogenic activity by modulating
MMP-2 expression, but not MMP-2 activity, to subsequently suppress tumor growth,
suggesting an important role for MMP-2 expression rather than MMP-2 activity in
anti-angiogenesis.

PMCID: PMC3335789
PMID: 22545131 [PubMed - in process]