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Published on: January 20, 2023
Inhibition of heat shock protein 27 (HspB1) tumorigenic functions by peptide aptamers
B Gibert1, E Hadchity, A Czekalla
1Centre de Génétique Moléculaire et Cellulaire, CNRS UMR5534, Université Lyon 1, Université de Lyon, Lyon, France.
Abstract:
Human heat shock protein 27 (Hsp27, HspB1) is an anti-apoptotic protein characterized for its tumorigenic and metastatic properties, and now referenced as a major therapeutic target in many types of cancer. Hsp27 biochemical properties rely on a structural oligomeric and dynamic organization. Downregulation by small interfering RNA or inhibition with dominant-negative mutant have proven their efficiency to counteract the anti-apoptotic and protective properties of Hsp27. In this study, we report the isolation and characterization of Hsp27-targeted molecules interfering with its structural organization. Using the peptide aptamer (PA) strategy, we isolated PAs that specifically interact with Hsp27 and not with the other members of the small heat shock protein family. In mammalian cell cultures, PAs expression perturbed the dimerization and oligomerization of Hsp27, and acted as negative regulators of the anti-apoptotic and cytoprotective activities of this protein. Further studies analyzing SQ20B cell xenografts in immunocompromised mice showed that PAs strongly reduced tumor development through cell cycle arrest. Our data suggest that PAs could provide a potential tool to develop strategies for the discovery of Hsp27 chemical inhibitors.
Insights
Researchers developed peptide aptamers (PAs) that disrupt the structure of human heat shock protein 27 (Hsp27). These PAs inhibit Hsp27
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Human heat shock protein 27 (Hsp27, HspB1) is an anti-apoptotic protein implicated in cancer tumorigenesis and metastasis.
- Hsp27's function is linked to its dynamic oligomeric structure, making it a significant therapeutic target.
- Previous strategies like siRNA and dominant-negative mutants have shown promise in counteracting Hsp27's effects.
Purpose of the Study:
- To isolate and characterize novel molecules that specifically target and interfere with the structural organization of Hsp27.
- To evaluate the efficacy of these molecules in disrupting Hsp27 oligomerization and its associated anti-apoptotic functions.
- To assess the therapeutic potential of these molecules in reducing tumor development in vivo.
Main Methods:
- Peptide aptamer (PA) strategy was employed to identify molecules with specific binding affinity to Hsp27.
- Mammalian cell cultures were used to study the effects of PA expression on Hsp27 dimerization and oligomerization.
- In vivo studies involved SQ20B cell xenografts in immunocompromised mice to evaluate tumor reduction.
Main Results:
- Peptide aptamers (PAs) specifically interacting with Hsp27 were successfully isolated.
- PA expression in cell cultures disrupted Hsp27 dimerization and oligomerization, inhibiting its anti-apoptotic and cytoprotective activities.
- In vivo, PAs significantly reduced tumor growth in SQ20B xenografts, inducing cell cycle arrest.
Conclusions:
- The isolated PAs effectively target Hsp27's structural organization and inhibit its oncogenic functions.
- These PAs demonstrate potential as therapeutic agents for cancer by targeting Hsp27.
- The findings suggest PAs can serve as a valuable tool for developing novel chemical inhibitors of Hsp27.
