BID and the α-bisabolol-triggered cell death program: converging on mitochondria and lysosomes

• Published in: Cell death & disease Vol. 10; no. 12; pp. 889 - 13
• Main Authors: Rigo, Antonella, Ferrarini, Isacco, Lorenzetto, Erika, Darra, Elena, Liparulo, Irene, Bergamini, Christian, Sissa, Cinzia, Cavalieri, Elisabetta, Vinante, Fabrizio
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26-11-2019; Springer Nature B.V
• Subjects: 14/19; 14/34; 14/63; 42/109; 42/89; 631/67/1059; 692/308/2778; 82; 82/1; 96/31; Animal models; Antibodies; Apoptosis; Apoptosis - drug effects; Autophagy - drug effects; Benzimidazoles - pharmacology; BH3 Interacting Domain Death Agonist Protein - metabolism; Biochemistry; Biomedical and Life Sciences; Blood cells; Carbocyanines - pharmacology; Cathepsin B; Cell Biology; Cell Culture; Cell Cycle - drug effects; Cell death; Cell Line; Cytosol; Cytotoxicity; Flow cytometry; G(M1) Ganglioside - metabolism; Gene Knockdown Techniques; Humans; Immunology; Life Sciences; Lipid bilayers; Lipid rafts; Lysosomes; Lysosomes - drug effects; Lysosomes - metabolism; Membrane Microdomains - metabolism; Membrane potential; Membrane Potential, Mitochondrial - drug effects; Membrane Proteins - metabolism; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Monocyclic Sesquiterpenes - pharmacology; Organelles; Plants; Protein Transport - drug effects; Transformed cells; Tumor cell lines; Western blotting
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-019-2126-8

α-Bisabolol (BSB) is a plant-derived sesquiterpene alcohol able to trigger regulated cell death in transformed cells, while deprived of the general toxicity in several mouse models. Here, we investigated the involvement of lysosomal and mitochondrial compartments in the cytotoxic effects of BSB, with a specific focus on the BH3-only activator protein BID. We found that BSB particularly accumulated in cancer cell lines, displaying a higher amount of lipid rafts as compared to normal blood cells. By means of western blotting and microscopy techniques, we documented rapid BSB-induced BID translocation to lysosomes and mitochondria, both of them becoming dysfunctional. Lysosomal membranes were permeabilized, thus blocking the cytoprotective autophagic flux and provoking cathepsin B leakage into the cytosol. Multiple flow cytometry-based experiments demonstrated the loss of mitochondrial membrane potential due to pore formation across the lipid bilayer. These parallel events converged on neoplastic cell death, an outcome significantly prevented by BID knockdown. Therefore, BSB promoted BID redistribution to the cell death executioner organelles, which in turn activated anti-autophagic and proapoptotic mechanisms. This is an example of how xenohormesis can be exploited to modulate basic cellular programs in cancer.