Type

Journal Article

Authors

J H M Prehn
D Kögel
A Strasser
A Villunger
M W Ward
N Thurow
C Bonner
B M Murphy
Claus Reimertz
B F Koehler
and 1 others

Subjects

Biochemistry

Topics
molecular sequence data proteasome inhibitors apoptosis metabolism protein folding dna primers base sequence bbc3 protein human humans proto oncogene proteins oligonucleotide array sequence analysis tumor suppressor protein p53 apoptosis regulatory proteins cell line tumor

Apoptosis induced by proteasome inhibition in cancer cells: predominant role of the p53/PUMA pathway. (2006)

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.
Collections Ireland -> Royal College of Surgeons in Ireland -> PubMed

Full list of authors on original publication

J H M Prehn, D Kögel, A Strasser, A Villunger, M W Ward, N Thurow, C Bonner, B M Murphy, Claus Reimertz, B F Koehler and 1 others

Experts in our system

1
Jochen H M Prehn
Royal College of Surgeons in Ireland
Total Publications: 206
 
2
Donat Kögel
Royal College of Surgeons in Ireland
Total Publications: 14
 
3
Andreas Strasser
Royal College of Surgeons in Ireland
Total Publications: 7
 
4
Brona M Murphy
Royal College of Surgeons in Ireland
Total Publications: 14