Bortezomib inhibits PKR-like endoplasmic reticulum (ER) kinase and induces apoptosis via ER stress in human pancreatic cancer cells

Steffan T. Nawrocki, Jennifer S. Carew, Kenneth Dunner, Lawrence H. Boise, Paul J. Chiao, Peng Huang, James L. Abbruzzese, David McConkey

Research output: Contribution to journalArticle

Abstract

Bortezomib (Velcade, formerly known as PS-341) is a boronic acid dipeptide derivative that is a selective and potent inhibitor of the proteasome. We hypothesized that proteasome inhibition would lead to an accumulation of misfolded proteins in the cell resulting in endoplasmic reticulum (ER) stress. The ability of bortezomib to induce ER stress and the unfolded protein response was investigated in a human pancreatic cancer cell line, L3.6p1. Bortezomib increased expression of ER stress markers, CHOP and BiP, but inhibited PKR-like ER kinase and subsequent phosphorylation of eukaryotic initiation factor 2α (eif2α), both of which are key events in translational suppression. These effects resulted in an accumulation of ubiquitylated proteins leading to protein aggregation and proteotoxicity. Peptide inhibitor or small interfering RNA targeting ER-resident caspase-4 blocked DNA fragmentation, establishing a central role for caspase-4 in bortezomib-induced cell death. The translation inhibitor cycloheximide abrogated bortezomib-induced protein aggregation, caspase-4 processing, and all other characteristics of apoptosis. Because malignant cells have higher protein synthesis rates than normal cells, they may be more prone to protein aggregation and proteotoxicity and possess increased sensitivity to bortezomib-induced apoptosis. Taken together, the results show that bortezomib induces a unique type of ER stress compared with other ER stress agents characterized by an absence of eif2α phosphorylation, ubiquitylated protein accumulation, and proteotoxicity.

Original languageEnglish (US)
Pages (from-to)11510-11519
Number of pages10
JournalCancer Research
Volume65
Issue number24
DOIs
StatePublished - Dec 15 2005
Externally publishedYes

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Endoplasmic Reticulum Stress
Pancreatic Neoplasms
Endoplasmic Reticulum
Phosphotransferases
Apoptosis
Caspases
Eukaryotic Initiation Factor-2
Proteins
Phosphorylation
Boronic Acids
Unfolded Protein Response
Bortezomib
Proteasome Inhibitors
Dipeptides
DNA Fragmentation
Proteasome Endopeptidase Complex
Cycloheximide
Heat-Shock Proteins
Small Interfering RNA
Cell Death

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Bortezomib inhibits PKR-like endoplasmic reticulum (ER) kinase and induces apoptosis via ER stress in human pancreatic cancer cells. / Nawrocki, Steffan T.; Carew, Jennifer S.; Dunner, Kenneth; Boise, Lawrence H.; Chiao, Paul J.; Huang, Peng; Abbruzzese, James L.; McConkey, David.

In: Cancer Research, Vol. 65, No. 24, 15.12.2005, p. 11510-11519.

Research output: Contribution to journalArticle

Nawrocki, Steffan T. ; Carew, Jennifer S. ; Dunner, Kenneth ; Boise, Lawrence H. ; Chiao, Paul J. ; Huang, Peng ; Abbruzzese, James L. ; McConkey, David. / Bortezomib inhibits PKR-like endoplasmic reticulum (ER) kinase and induces apoptosis via ER stress in human pancreatic cancer cells. In: Cancer Research. 2005 ; Vol. 65, No. 24. pp. 11510-11519.
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