Abstract
Recently, the research community has become increasingly concerned with the receptor αvβ5, a member of the well-known integrin family. Different ongoing studies have evidenced that αvβ5 integrin regulates not only physiological processes but also a wide array of pathological events, suggesting the receptor as a valuable biomarker to specifically target for therapeutic/diagnostic purposes. Remarkably, in some tumors the involvement of the receptor in cell proliferation, tumor dissemination and angiogenesis is well-documented. In this scenario, the availability of a selective αvβ5 antagonist without ‘off-target’ protein effects may improve survival rate in patients with highly aggressive tumors, such as hepatocellular carcinoma. We recently reported a cyclic peptide, RGDechi15D, obtained by structure-activity studies. To our knowledge it represents the first peptide-based molecule reported in the literature able to specifically bind αvβ5 integrin and not cross react with αvβ3. Here we demonstrated the ability of the peptide to diminish both adhesion and invasion of HepG2 cells, an in vitro model system for hepatocellular carcinoma, to reduce the cell proliferation through an apoptotic process, and to interfere with the PI3K pathway. The peptide, also decreases the formation of new vessels in endothelial cells. Taken together these results indicate that the peptide can be considered a promising molecule with properties suited to be assessed in the future for its validation as a selective therapeutic/diagnostic weapon in hepatocarcinoma.
Highlights
Integrins are transmembrane receptors able to dictate cellular responses to a variety of inputs thanks to their capacity to differentially recognize distinct environments
By this combined approach we demonstrated that the substitution of the key homocitrulline residue with aspartic acid shifts the receptor binding selectivity from αvβ3 to αvβ5 integrin, identifying a novel and selective αvβ5 ligand, named RGDechi15D [36]
The expression levels of αvβ5 and αvβ3 integrins on surface of HepG2 were determined by
Summary
Integrins are transmembrane receptors able to dictate cellular responses to a variety of inputs thanks to their capacity to differentially recognize distinct environments. To allow for this flexibility, integrins are comprised of 18 α and 8 β subunits that pair to form at least 24 different functional heterodimeric receptors. They can transduce extracellular stimuli resulting in an extensive range of downstream effects on cell adhesion, migration, proliferation, differentiation and apoptosis [1]. The αv subunit, which forms heterodimers with β1, β3, β5, β6 or β8 subunits, is able to recognize more extracellular matrix (ECM) ligands and growth factors thanks to the RGD sequence.
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