Title:Antiangiogenic Function of Antithrombin is Dependent on its Conformational Variation: Implication for Other Serpins
Volume: 20
Issue: 4
Author(s): Asim Azhar, Poonam Singh, Qudsia Rashid, Asma Naseem, Mohammad Sazzad Khan and Mohamad Aman Jairajpuri
Affiliation:
Keywords:
Angiogenesis, antiangiogenic proteins, antithrombin, heparin binding, reactive center loop, serpin, tumor cell, metastasis, coagulation, endothelial cell
Abstract: Endogenous angiogenesis inhibitor that specifically decreases tumor cell proliferation can be used to treat cancer
since angiogenesis is required at every step of tumor progression and metastasis. Endothelial cells are the main target
for the antiangiogenic therapy because they are non-transformed and easily accessible to angiogenic inhibitors. Antithrombin
functions as a principal plasma protein inhibitor of blood coagulation proteinases and belongs to the family of
serine protease inhibitors (serpins) which have common mechanism of inhibition. Antithrombin acquires a potent antiangiogenic
activity upon conversion of the native molecule to cleaved or latent conformation. Cleaved and latent preparations
of bovine and human plasma derived antithrombin inhibits capillary endothelial cell proliferation and the growth of
human SK-NAS neuroblastoma and Lewis lung carcinoma tumors in mice but not the native antithrombin’s. The native
form of antithrombin binds with high affinity to vascular heparan sulfate proteoglycans containing a specific pentasaccharide
sequence and it is this cofactor interaction that activates antithrombin to maximal rate of thrombin inhibition. Upon
inhibitory complex formation with target proteinases the antithrombin undergoes stressed to relaxed transformation and
lose their high affinity for pentasacchride. Low affinity relaxed conformation with reduced heparin binding like cleaved
and latent are antiangiogenic but native high affinity heparin binding stressed conformation is not, indicating the critical
importance of heparin affinity in antithrombin antiangiogenic function. Based on evidence of interactions of the endothelial
cell growth factors bFGF (basic fibroblast growth factor) and VEGF (vascular endothelial cell growth factor) with
heparin like molecule in matrix, the possibility of antiangiogenic antithrombin to interfere with endothelial cell growth
and angiogenesis through heparin mediated mechanism deserves serious consideration and investigation. It is also possible
that cleaved and latent conformations with reduced affinity for heparins can also induce conformational change in the
antithrombin which can open an epitope on the antithrombin surface for appropriate interactions on the endothelial surface
for better antiangiogenic activity. This review illustrates the potential of antithrombin and other serpin family members as
endogenous antiangiogenic proteins.