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Keywords:

  • p62;
  • MG132;
  • caspase-8;
  • U87MG;
  • proteasome inhibition

Abstract

Glioblastoma multiforme (GBM) is the most common and lethal type of brain cancer. Proteasome inhibitors are emerging as a new class of anti-glioma agents; however, the mechanisms of their killing malignant cells are still unclear. We treated U87MG cells with the proteasome inhibitor MG132 and found that cell death correlated with caspase-8 activation and autophagy protein p62/SQSTM1.To explore the role of autophagy and p62/SQSTM1 in MG132-induced cancer cell death, we measured the alteration of MG132's cytotoxicity by autophagy inhibition, autophagy induction or variation of p62/SQSTM1 gene expression. Autophagy was activated upon MG132 treatment for short periods, while inhibition of autophagy aggravated MG132-induced cell death followed by high levels of p62/SQSTM1 and active caspase-8 (p18). Moreover, U87MG cell death was dependent on p62/SQSTM1, and its function required its C-terminus UBA domain to attenuate the MG132-induced cell death. The results suggest that p62/SQSTM1 is a potential contributor in determining the fate of U87MG cells deficient in proteolytic activity.