An inhibition of p62/SQSTM1 caused autophagic cell death of several human carcinoma cells

Abstract

p62/SQSTM1 (p62) is a multifunctional protein implicated in several signal transduction pathways and selectively degraded by autophagy, a process for lysosomal degradation of both protein and organelle. p62 was also recently reported to be overexpressed in various malignancies and its inhibition to suppress carcinoma cell proliferation. However, its correlation with autophagy in carcinoma cells has remained largely unknown. Therefore, in this study, we examined the effects of p62 inhibition on the regulation of autophagy and cell survival in p62-positive carcinoma cells. p62-silencing dramatically suppressed cell proliferation and induced autophagy in p62 expressing PC9 and A549 cells. 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.

Disruption of the ribosomal P complex leads to stress-induced autophagy

“…Additional markers of autophagy such as levels of SQSTM1/p62 degradation were analyzed. 25,26 Indeed, SQSTM1 degradation occurred in cells induced to express RPLP0 shRNA, RPLP1 shRNA, RPLP2 shRNA vs. NT shRNAexpressing cells (Fig. 2B).…”

Targeting Programmed Cell Death Using Small‐Molecule Compounds to Improve Potential Cancer Therapy

“…13 Having been studied extensively for accurate mechanisms to distinguish the cytoprotective form and autophagic cell death still need to be addressed, there is evidence showing that both excessive activation of autophagy and the selective removal of autophagy substrates can lead to autophagic cell death. [22][23][24] Notably, according to the definition criteria proposed by the Nomenclature Committee on Cell Death (NCCD), the term "autophagic cell death" can only be used for cell death that are mediated by autophagy and can be suppressed by the inhibition of the autophagic pathway. 25 As a double-edged sword, utilization of autophagy regulating compounds in cancer treatment can now either be related to cytoprotective autophagy or autophagic cell death, depending on the context.…”

“…It is proposed that the prosurvival or prodeath role of autophagy may be causally related to the extent and duration of autophagy, which indicates that there is a threshold effect of autophagy . Although accurate mechanisms to distinguish the cytoprotective form and autophagic cell death still need to be addressed, there is evidence showing that both excessive activation of autophagy and the selective removal of autophagy substrates can lead to autophagic cell death . Notably, according to the definition criteria proposed by the Nomenclature Committee on Cell Death (NCCD), the term “autophagic cell death” can only be used for cell death that are mediated by autophagy and can be suppressed by the inhibition of the autophagic pathway .…”

Phenolic compounds stage an interplay between the ubiquitin–proteasome system and ubiquitin signal autophagic degradation for the ubiquitin-based cancer chemoprevention

“…Similar to MG132-treated cells, tannic acid inhibited 26S proteasome but not autophagic pathway to cause cell apoptosis. The suppressed cell viability of p62-silenced cells was restored by autophagy inhibitor 3-methyladenine (3-MA, PI3K III inhibitor), but not chloroquine (autophagy-lysosomal inhibitor) (Nihira, Miki, Ono, Suzuki, & Sasano, 2014). An inhibition of p62 resulted in the formation of mis-regulated autophagosomes with multilayer membranes and an autophagic cell death (Nihira et al, 2014).…”

“…There are higher increased ratio of p62 levels and lower decreased ratio of USP47 levels in M + G + E-treated cells when compared to tannic acid-treated cells. p62 resulted in the formation of regulated autophagosomes (Nihira et al, 2014). USP47 stabilizes newly synthesized cytoplasmic Pol β, which serves as a source for nuclear Pol β in DNA repair (Parsons et al, 2011).…”