Celecoxib transiently inhibits cellular protein synthesis

Peter Pyrko, Adel Kardosh, Axel H. Schönthal

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

To uncover the full spectrum of its pharmacological activities, the selective COX-2 inhibitor celecoxib is routinely being used at concentrations of up to 100 μM in cell culture. At these elevated concentrations, several COX-2-independent effects were identified, although many details of these events have remained unclear. Here, we report a COX-2-independent effect of celecoxib that might have profound consequences for the interpretation of previous results obtained at elevated concentrations of this drug in vitro. We found that celecoxib rapidly inhibits general protein translation at concentrations as low as 30 μM. This appears to be a consequence of endoplasmic reticulum (ER) stress and entails the phosphorylation and inactivation of eukaryotic translation initiation factor 2 alpha (eIF2α). These effects were not achieved by other coxibs (rofecoxib, valdecoxib) or traditional NSAIDs (indomethacin, flurbiprofen), but were mimicked by the COX-2-inactive celecoxib analog, 2,5-dimethyl-celecoxib (DMC), indicating COX-2 independence. Considering the obvious impact of blocked translation on cellular function, we provide evidence that this severe inhibition of protein synthesis might suffice to explain some of the previously reported COX-2-independent effects of celecoxib, such as the down-regulation of the essential cell cycle regulatory protein cyclin D, which is a short-lived protein that rapidly disappears in response to the inhibition of protein synthesis. Taken together, our findings establish ER stress-induced inhibition of general translation as a critical outcome of celecoxib treatment in vitro, and suggest that this effect needs to be considered when interpreting observations from the use of this drug in cell culture.

Original languageEnglish (US)
Pages (from-to)395-404
Number of pages10
JournalBiochemical Pharmacology
Volume75
Issue number2
DOIs
StatePublished - Jan 15 2008
Externally publishedYes

Fingerprint

Celecoxib
Proteins
Endoplasmic Reticulum Stress
Cyclooxygenase 2 Inhibitors
Cell culture
Prokaryotic Initiation Factor-2
Cell Culture Techniques
Eukaryotic Initiation Factor-2
Cyclin D
Flurbiprofen
Eukaryotic Initiation Factors
Cell Cycle Proteins
Phosphorylation
Protein Biosynthesis
Non-Steroidal Anti-Inflammatory Agents
Indomethacin
Pharmaceutical Preparations
Down-Regulation
Pharmacology

Keywords

  • Coxibs
  • Cyclin D
  • Dimethyl-celecoxib
  • Endoplasmic reticulum stress
  • NSAIDs
  • Translation initiation factor 2 alpha

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

Cite this

Celecoxib transiently inhibits cellular protein synthesis. / Pyrko, Peter; Kardosh, Adel; Schönthal, Axel H.

In: Biochemical Pharmacology, Vol. 75, No. 2, 15.01.2008, p. 395-404.

Research output: Contribution to journalArticle

Pyrko, Peter ; Kardosh, Adel ; Schönthal, Axel H. / Celecoxib transiently inhibits cellular protein synthesis. In: Biochemical Pharmacology. 2008 ; Vol. 75, No. 2. pp. 395-404.
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