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

Kaito Nihira, Yasuhiro Miki, Katsuhiko Ono, Takashi Suzuki, Hironobu Sasano

Research output: Contribution to journalArticlepeer-review

45 Citations (Scopus)

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. p62/SQSTM1 (p62) is a multifunctional protein implicated in several signal transduction pathways and selectively degraded by autophagy, a process for lysosomal degradation of protein and organelle. Results of our present study revealed that p62-silencing resulted in the formation of mis-regulated multilayer autophagosomes and an autophagic cell death, and p62 can therefore be an attractive target for the development of anti-neoplastic agents.

Original languageEnglish
Pages (from-to)568-575
Number of pages8
JournalCancer science
Volume105
Issue number5
DOIs
Publication statusPublished - 2014 May

Keywords

  • Autophagy
  • Cell death
  • Electron microscopy
  • P62
  • SQSTM1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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