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Inhibition of vacuolar ATP ase attenuates the TRAIL ‐induced activation of caspase‐8 and modulates the trafficking of TRAIL receptosomes
Author(s) -
Horova Vladimira,
Hradilova Nada,
Jelinkova Iva,
Koc Michal,
Svadlenka Jan,
Brazina Jan,
Klima Martin,
Slavik Josef,
Hyrslova Vaculova Alena,
Andera Ladislav
Publication year - 2013
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.12347
Subject(s) - microbiology and biotechnology , endosome , bafilomycin , apoptosis , caspase 8 , caspase , receptor , programmed cell death , chemistry , biology , biochemistry , autophagy
Tumour necrosis factor ( TNF ) related apoptosis inducing ligand ( TRAIL ), a membrane‐bound ligand from the TNF family, has attracted significant attention due to its rather specific and effective ability to induce apoptotic death in various types of cancer cells via binding to and activating its pro‐apoptotic death receptors. However, a significant number of primary cancer cells often develop resistance to TRAIL treatment, and the signalling platform behind this phenomenon is not fully understood. Upon blocking endosomal acidification by the vacuolar ATP ase ( V ‐ ATP ase) inhibitors bafilomycin A1 (BafA1) or concanamycin A, we observed a significantly reduced initial sensitivity of several, mainly colorectal, tumour cell lines to TRAIL ‐induced apoptosis. In cells pretreated with these inhibitors, the TRAIL ‐induced processing of caspase‐8 and the aggregation and trafficking of the TRAIL receptor complexes were temporarily attenuated. Nuclear factor κB or mitogen activated protein/stress kinase signalling from the activated TRAIL receptors remained unchanged, and neither possible lysosomal permeabilization nor acid sphingomyelinase was involved in this process. The cell surface expression of TRAIL receptors and their TRAIL ‐induced internalization were not affected by V ‐ ATP ase inhibitors. The inhibitory effect of BafA1, however, was blunted by knockdown of the caspase‐8 inhibitor c FLIP . Altogether, the data obtained provide the first evidence that endosomal acidification could represent an important regulatory node in the proximal part of TRAIL ‐induced pro‐apoptotic signalling. Structured digital abstractTRAIL and Caspase-8 colocalize by fluorescence microscopy ( View interaction ) TRAIL physically interacts with DR-5 , Caspase-10 , Caspase-8 , cFLIP and FADD by pull down ( View interaction )