A fusion antitumor peptide regulates proliferation and apoptosis of endothelial cells
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The present research has been carried out to elicit the mechanism of antiangiogenic activity of a fusion peptide P2. Peptide P2 was designed by the connection of a heptapeptide MMP inhibitor to ES-2, a fragment of Endostatin. In a previous study, P2 demonstrated strong antiangiogenic and antitumor effect, and the current work explains the antiangiogenic mechanism of P2 through endothelial cell proliferation and apoptosis. In our study, it was shown that P2 inhibited HUVECs proliferation at a low serum concentration and this effect might be achieved through arresting cell cycle by decreasing the expression level of Cyclin D1. In addition, P2 was found to induce apoptosis of HUVECs. Using Western blot, it was indicated that P2 induced the cleavage of Caspase-3, the hallmark protease of apoptosis. The activation and expression of the upstream regulator Caspase-9 can also be affected by P2 treatment. Furthermore, P2 reduced the protein level of antiangiogenic factors Bcl-xL and Bcl-2. These results revealed that P2 regulates endothelial cell apoptosis through intrinsic apoptotic pathway.
KeywordsFusion peptide Antiangiogenic mechanism Endothelial cell proliferation Endothelial apoptosis
The present study was supported by the National Natural Science Foundation of China (Grant Nos. 81301902 and 81773837) and Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).
Compliance with ethical standards
Conflict of interest
The authors declare that there is no conflict of interests regarding the publication of this paper.
All authors read and approved the final manuscript.
- Dallas SL, Rosser JL, Mundy GR, Bonewald LF (2002) Proteolysis of latent transforming growth factor-beta (TGF-beta)-binding protein-1 by osteoclasts. A cellular mechanism for release of TGF-beta from bone matrix. J Biol Chem 277:21352–21360. https://doi.org/10.1074/jbc.M111663200 CrossRefPubMedGoogle Scholar
- Folkman J (2006a) Angiogenesis. Annu Rev Med 57:1–18. https://doi.org/10.1146/annurev.med.57.121304.131306 CrossRefPubMedGoogle Scholar
- Ikeda M et al (2000) Inhibition of gelatinolytic activity in tumor tissues by synthetic matrix metalloproteinase inhibitor: application of film in situ zymography. Clin Cancer Res Off J Am Assoc Can Res 6:3290–3296Google Scholar
- O’Reilly MS et al. (1997) Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88:277–285Google Scholar
- Qiu Z et al (2012) Definition of peptide inhibitors from a synthetic peptide library by targeting gelatinase B/matrix metalloproteinase-9 (MMP-9) and TNF-alpha converting enzyme (TACE/ADAM-17). J Enzyme Inhib Med Chem 27:533–540. https://doi.org/10.3109/14756366.2011.599323 CrossRefPubMedGoogle Scholar
- Vandooren J et al (2015) Circular trimers of gelatinase B/matrix metalloproteinase-9 constitute a distinct population of functional enzyme molecules differentially regulated by tissue inhibitor of metalloproteinases-1. Biochem J 465:259–270. https://doi.org/10.1042/bj20140418 CrossRefPubMedPubMedCentralGoogle Scholar
- Wang J et al (2005) Results of randomized, multicenter, double-blind phase III trial of rh-endostatin (YH-16) in treatment of advanced non-small cell lung cancer patients. Chin J Lung Cancer 8:283–290. https://doi.org/10.3779/j.issn.1009-3419.2005.04.07 Google Scholar
- Yadav L, Puri N, Rastogi V, Satpute P, Sharma V (2015) Tumour angiogenesis and angiogenic inhibitors: a review. JCDR 9:Xe01–Xe05. https://doi.org/10.7860/jcdr/2015/12016.6135