Apoptosis induced by proteasome inhibition in cancer cells: Predominant role of the p53/PUMA pathway

C. G. Concannon, B. F. Koehler, Claus Reimertz, B. M. Murphy, C. Bonner, N. Thurow, M. W. Ward, A. Villunger, A. Strasser, D. Kögel, J. H.M. Prehn*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

82 Scopus citations

Abstract

The proteasome has emerged as a novel target for antineoplastic treatment of hematological malignancies and solid tumors, including those of the central nervous system. To identify cell death pathways activated in response to inhibition of the proteasome system in cancer cells, we treated human SH-SY5Y neuroblastoma cells with the selective proteasome inhibitor (PI) epoxomicin (Epoxo). Prolonged exposure to Epoxo was associated with increased levels of poly-ubiquitinylated proteins and p53, release of cytochrome c from the mitochondria, and activation of caspases. Analysis of global gene expression using high-density oligonucleotide microarrays revealed that Epoxo triggered transcriptional activation of the two Bcl-2-homology domain-3-only (BH3-only) genes p53 upregulated modulator of apoptosis (PUMA) and Bim. Subsequent studies in PUMA- and Bim-deficient cells indicated that Epoxo-induced caspase activation and apoptosis was predominantly PUMA-dependent. Further characterization of the transcriptional response to Epoxo in HCT116 human colon cancer cells demonstrated that PUMA induction was p53-dependent; with deficiency in either p53 or PUMA significantly protected HCT116 cells against Epoxo-induced apoptosis. Our data suggest that p53 activation and the transcriptional induction of its target gene PUMA play an important role in the sensitivity of cancer cells to apoptosis induced by proteasome inhibition, and imply that antineoplastic therapies with PIs might be especially useful in cancers with functional p53.

Original languageEnglish (US)
Pages (from-to)1681-1692
Number of pages12
JournalOncogene
Volume26
Issue number12
DOIs
StatePublished - Mar 15 2007
Externally publishedYes

Bibliographical note

Funding Information:
The authors wish to thank Drs B Vogelstein, L Zhang, and J Yu for p53 and PUMA-deficient cells and Drs P Bouillet and J Adams for gifts of knockout mice. This study was supported by grants from the DFG (PR 338/9-3 and 9-4) to JHMP and DK and Science Foundation Ireland (03/RP/B344) to JHMP.

Keywords

  • Apoptosis
  • BH3-only protein
  • Bcl-2 family
  • Epoxomicin
  • Proteasome
  • p53

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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