A synthetic BMP-2 mimicking peptide induces glioblastoma stem cell differentiation

• Published in: Biochimica et biophysica acta. General subjects Vol. 1861; no. 9; pp. 2282 - 2292
• Main Authors: Rampazzo, Elena, Dettin, Monica, Maule, Francesca, Scabello, Alessandra, Calvanese, Luisa, D’Auria, Gabriella, Falcigno, Lucia, Porcù, Elena, Zamuner, Annj, Della Puppa, Alessandro, Boso, Daniele, Basso, Giuseppe, Persano, Luca
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.09.2017
• Subjects: antineoplastic agents; Antineoplastic Agents - pharmacology; Astrocytes - cytology; Astrocytes - drug effects; BMP signalling; BMP-2 mimic; bone formation; Bone Morphogenetic Protein 2 - chemistry; Bone Morphogenetic Protein 2 - pharmacology; bone morphogenetic proteins; brain neoplasms; cell differentiation; Cell Differentiation - drug effects; Dacarbazine - analogs & derivatives; Dacarbazine - pharmacology; drug therapy; epitopes; GBMP1a; Glial differentiation; Glioblastoma; Glioblastoma - pathology; Humans; luciferase; Mesenchymal Stromal Cells - cytology; Mesenchymal Stromal Cells - drug effects; Molecular Mimicry; Neoplastic Stem Cells - cytology; Neoplastic Stem Cells - drug effects; nuclear magnetic resonance spectroscopy; Osteogenesis - drug effects; Peptide Fragments - chemistry; Peptide Fragments - pharmacology; peptides; phosphorylation; prediction; stem cells; Western blotting; GBMP1a; BMP signalling; Glial differentiation; BMP-2 mimic; Glioblastoma
• ISSN: 0304-4165; 1872-8006
• DOI: 10.1016/j.bbagen.2017.07.001

Glioblastoma (GBM) is the most aggressive type of primary brain tumor, characterized by the intrinsic resistance to chemotherapy due to the presence of a highly aggressive Cancer Stem Cell (CSC) sub-population. In this context, Bone Morphogenetic Proteins (BMPs) have been demonstrated to induce CSC differentiation and to sensitize GBM cells to treatments. The BMP-2 mimicking peptide, named GBMP1a, was synthesized on solid-phase by Fmoc chemistry. Structural characterization and prediction of receptor binding were obtained by Circular Dicroism (CD) and NRM analyses. Activation of BMP signalling was evaluated by a luciferase reporter assay and western blot. Pro-differentiating effects of GBMP1a were verified by immunostaining and neurosphere assay in primary glioblastoma cultures. CD and NMR showed that GBMP1a correctly folds into expected tridimensional structures and predicted its binding to BMPR-IA to the same epitope as in the native complex. Reporter analysis disclosed that GBMP1a is able to activate BMP signalling in GBM cells. Moreover, BMP-signalling activation was specifically dependent on smad1/5/8 phosphorylation. Finally, we confirmed that GBMP1a treatment is sufficient to enhance osteogenic differentiation of Mesenchymal Stem Cells and to induce astroglial differentiation of glioma stem cells (GSCs) in vitro. GBMP1a was demonstrated to be a good inducer of GSC differentiation, thus being considered a potential anti-cancer tool to be further developed for GBM treatment. These data highlight the role of BMP-mimicking peptides as potential anti-cancer agents against GBM and stimulate the further development of GBMP1a-based structures in order to enhance its stability and activity. [Display omitted] •BMP-2 has been shown to promote differentiation of glioblastoma stem cells.•GBMP1a well mimics the structure of the BMP-2 wrist epitope able to bind BMPR-IA.•GBMP1a is predicted to bind to BMPR-IA to the same epitope as in the native complex.•GBMP1a activates BMP signalling via Smad1/5/8 phosphorylation.•GBMP1a promotes glial differentiation of GSCs and sensitization to temozolomide.