Delineation of crosstalk between HSP27 and MMP-2/MMP-9: A synergistic therapeutic avenue for glioblastoma management

• Published in: Biochimica et biophysica acta. General subjects Vol. 1863; no. 7; pp. 1196 - 1209
• Main Authors: Rajesh, Y., Banerjee, Anupam, Pal, Ipsita, Biswas, Angana, Das, Subhayan, Dey, Kaushik Kumar, Kapoor, Neelkamal, Ghosh, Ananta Kumar, Mitra, Pralay, Mandal, Mahitosh
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.07.2019
• Subjects: binding sites; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Brain Neoplasms - therapy; Cell Line, Tumor; cell lines; Disease Progression; drugs; epithelium; extracellular matrix; Glioblastoma; Glioblastoma - metabolism; Glioblastoma - pathology; Glioblastoma - therapy; heat shock proteins; HSP27; HSP27 Heat-Shock Proteins - metabolism; Humans; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 8 - metabolism; mechanistic models; metalloproteinases; MMP-2; MMP-9; patients; precipitin tests; prediction; site-directed mutagenesis; Therapeutic target; therapeutics; MMP-2; MMP-9; Therapeutic target; Glioblastoma; HSP27
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2019.04.015

Epithelial to mesenchymal transition (EMT) and extracellular matrix (ECM) remodeling, are the two elemental processes promoting glioblastoma (GBM). In the present work we propose a mechanistic modelling of GBM and in process establish a hypothesis elucidating critical crosstalk between heat shock proteins (HSPs) and matrix metalloproteinases (MMPs) with synergistic upregulation of EMT-like process and ECM remodeling. The interaction and the precise binding site between the HSP and MMP proteins was assayed computationally, in-vitro and in GBM clinical samples. A positive crosstalk of HSP27 with MMP-2 and MMP-9 was established in both GBM patient tissues and cell-lines. This association was found to be of prime significance for ECM remodeling and promotion of EMT-like characteristics. In-silico predictions revealed 3 plausible interaction sites of HSP27 interacting with MMP-2 and MMP-9. Site-directed mutagenesis followed by in-vitro immunoprecipitation assay (IP) with 3 mutated recombinant HSP27, confirmed an interface stretch containing residues 29–40 of HSP27 to be a common interaction site for both MMP-2 and MMP-9. This was further validated with in-vitro IP of truncated (sans AA 29–40) recombinant HSP27 with MMP-2 and MMP-9. The association of HSP27 with MMP-2 and MMP-9 proteins along with the identified interacting stretch has the potential to contribute towards drug development to inhibit GBM infiltration and migration. Current findings provide a novel therapeutic target for GBM opening a new horizon in the field of GBM management. [Display omitted] •Root cause for glioblastoma high infiltrative potential is yet unknown and no clear way to prevent it.•Association between MMPs and HSPs with infiltrative potential was revealed by deciphering novel and vital interaction among of HSP27 with MMP-2 and MMP-9.•Study presented HSP27 promoting EMT-like features in glioblastoma tumor cells through a direct interaction with MMP-2 and MMP-9 at an interface site AA29–40 of HSP27.•Our findings contribute towards precise drug development for inhibiting GBM infiltration and migration.