ConBr lectin modulates MAPKs and Akt pathways and triggers autophagic glioma cell death by a mechanism dependent upon caspase-8 activation.

Abstract

Glioblastoma multiforme is the most aggressive type of glioma, with limited treatment and poor prognosis. Despite some advances over the last decade, validation of novel and selective antiglioma agents remains a challenge in clinical pharmacology. Prior studies have shown that leguminous lectins may exert various biological effects, including antitumor properties. Accordingly, this study aimed to evaluate the mechanisms underlying the antiglioma activity of ConBr, a lectin extracted from the Canavalia brasiliensis seeds. ConBr at lower concentrations inhibited C6 glioma cell migration while higher levels promoted cell death dependent upon carbohydrate recognition domain (CRD) structure. ConBr increased p38MAPK and JNK and decreased ERK1/2 and Akt phosphorylation. Moreover, ConBr inhibited mTORC1 phosphorylation associated with accumulation of autophagic markers, such as acidic vacuoles and LC3 cleavage. Inhibition of early steps of autophagy with 3-methyl-adenine (3-MA) partially protected whereas the later autophagy inhibitor Chloroquine (CQ) had no protective effect upon ConBr cytotoxicity. ConBr also augmented caspase-3 activation without affecting mitochondrial function. Noteworthy, the caspase-8 inhibitor IETF-fmk attenuated ConBr induced autophagy and C6 glioma cell death. Finally, ConBr did not show cytotoxicity against primary astrocytes, suggesting a selective antiglioma activity. In summary, our results indicate that ConBr requires functional CRD lectin domain to exert antiglioma activity, and its cytotoxicity is associated with MAPKs and Akt pathways modulation and autophagy- and caspase-8- dependent cell death.

• Authors: Ingrid A V Wolin, Isabella A Heinrich, Ana Paula M Nascimento, Priscilla G Welter, Liliana Del V Sosa, Ana Lucia De Paul, Alfeu Zanotto-Filho, Cláudia Beatriz Nedel, Lara Dias Lima, Vinicius Jose Silva Osterne, Vanir Reis Pinto-Junior, Kyria S Nascimento, Benildo S Cavada, Rodrigo B Leal
• Journal: Biochimie (Biochimie) Vol. 180 Pg. 186-204 (Jan 2021) ISSN: 1638-6183 [Electronic] France
• PMID: 33171216 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Chemical References

• Antineoplastic Agents
• Plant Lectins
• Polysaccharides
• lectin, Canavalia
• Proto-Oncogene Proteins c-akt
• Mitogen-Activated Protein Kinases
• Casp3 protein, rat
• Casp8 protein, rat
• Caspase 3
• Caspase 8

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Astrocytes (drug effects)
• Autophagy (drug effects)
• Caspase 3 (metabolism)
• Caspase 8 (metabolism)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Survival (drug effects)
• Enzyme Activation (drug effects)
• Glioma (drug therapy, metabolism, pathology)
• Humans
• MAP Kinase Signaling System (drug effects)
• Mice
• Mitochondria (drug effects)
• Mitogen-Activated Protein Kinases (metabolism)
• Molecular Docking Simulation
• Plant Lectins (pharmacology)
• Polysaccharides (metabolism)
• Protein Domains (physiology)
• Protein Structure, Quaternary (physiology)
• Protein Structure, Tertiary (physiology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats