Cardiovascular Research Advance Access [Accepted Manuscript] published online on March 14, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn072
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Tissue inhibitor of metalloproteinases-3 interacts with angiotensin II type 2 receptor and additively inhibits angiogenesis
a Research Institute, National Cancer Center, 809, Madu 1-dong, Ilsan-gu, Goyang-si, Gyeonggi-do 411-769, Korea
b Center for Uterine Cancer, Research Institute and Hospital, National Cancer Center, 809, Madu 1-dong, Ilsan-gu, Goyang-si, Gyeonggi-do 411-769, Korea
c Molecular Therapy Research Center, Sungkyunkwan University, Samsung Medical Center Annex 8F, 50, Ilwon-Dong, Kangnam-Ku, Seoul 135-710, Korea
d Division of Gynecologic Oncology, Department of Obstertrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50, Ilwon-Dong, Kangnam-Ku, Seoul 135-710, Korea
* Corresponding authors: Rho is to be contacted at Tel.: +82-31-920-2383; fax: +82-31-920-2337, Lee, Tel.: +82-2-3410-3510; fax: +82-2-3410-6829; E-mail: sbrho{at}ncc.re.kr (S. B. Rho), jeholee{at}gmail.com (J.-H. Lee)
Aim: The tissue inhibitors of metalloproteinases (TIMPs) are complex molecules with both pro- and anti-tumor effects. Thus, their diverse expression could be due to their multifunctional properties with respect to tumor growth, angiogenesis, apoptosis, and other biological functions. Previous data have shown that TIMPs bind tightly to most matrix metalloproteinases (MMPs), although the pathway mediating angiostatic activity has not been fully established.
Methods and Results: As an initial step to elucidate the mechanism that regulates TIMP-3, we used a yeast two-hybrid system to screen a human ovary cDNA library for a novel TIMP-3 interacting partner. Here, we identified human angiotensin II type 2 receptor (AGTR2) as such a partner, which is well known to be a regulator of cardiovascular homeostasis. In this present study, we investigated whether AGTR2-mediated apoptotic activity can inhibit the growth of ovarian cancer in an experimental model system. AGTR2 treatment was found to be more effective in inhibiting ovarian cancer growth than treatment with TIMP-3 in parallel experiments. Subsequently, the efficacy of the combined treatment with TIMP-3 and AGTR2 was investigated. In the presence of both of these proteins, vascular endothelial growth factor (VEGF)-induced human umbilical vein endothelial cell (HUVEC) proliferation was additively inhibited, and the inhibition of Akt and endothelial NO synthase phosphorylation was blocked.
Conclusions: These combined results suggest that two angiostatic molecules may have an important biological role in regulating potent antiangiogenic effects and possibly may have a role in anti-tumor therapy.
Time for primary review: 14 days