An inhibition of p62/SQSTM1 caused autophagic cell death of several human carcinoma cells.
Bottom Line: Electron microscopical analysis revealed the formation of autophagosomes with multilayer membranes caused by p62-silencing. p62 silencing-mediated reduced cell viability was restored by both genomic and pharmacological inhibition of autophagy but not that of apoptosis.These findings were also detected in several types of carcinoma cell lines including adenocarcinomas and squamous cell carcinomas.Results of our present study revealed that an inhibition of p62 resulted in the formation of mis-regulated autophagosomes with multilayer membranes and an autophagic cell death, and p62 can therefore be an attractive target for the development of anti-neoplastic agents.
Affiliation: Department of Pathology, School of Medicine, Tohoku University, Sendai, Japan.Show MeSH
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Mentions: Previous reports revealed that p62 activates several signal transduction pathways regulating apoptosis. Therefore, in this study, we examined the potential contribution of apoptosis to reduced cell viability induced by p62 inhibition. Both sip62s markedly increased cell death in PC9 and A549 cells in a siRNAs concentration dependent manner (Fig.5a, Fig. S3). The cleavage of two apoptosis markers, Caspase-3 and PARP (poly ADP ribose polymerase), was slightly increased in the cells transfected with sip62s (Fig.5b). However, pan-caspase inhibitor Z-VAD-FMK did not necessarily restore cell viability decreased by p62-silencing (Fig.5c). These results indicated that p62 inhibition strongly induced cell death, mainly as a result of autophagic cell death.
Affiliation: Department of Pathology, School of Medicine, Tohoku University, Sendai, Japan.