Anti-apoptotic Bcl-2 fails to form efficient complexes with pro-apoptotic Bak to protect from Celecoxib-induced apoptosis.

Abstract

The non-steroidal anti-inflammatory drug Celecoxib is a specific inhibitor of cyclooxygenase-2. Apart from its inhibitor function, Celecoxib induces apoptosis through the intrinsic pathway which is controlled by the Bcl-2 family members. In Jurkat T lymphoma cells, treatment with Celecoxib results in a rapid decline of the anti-apoptotic Bcl-2-related protein Mcl-1. The depletion of Mcl-1 is sufficient for apoptosis induction and can be blocked by overexpression of Bcl-xL but not by the close homologue Bcl-2. The present investigation analyzed the mechanism by which Bcl-xL prevents apoptosis induction whereas Bcl-2 failed to. Our data show that the involvement of the orphan nuclear receptor Nur77/TR3 specifically targeting Bcl-2 but not Bcl-xL was not involved in Celecoxib-induced apoptosis. Surprisingly, BH3-only proteins Bid, Bim, and Puma of the Bcl-2 family were not needed either. However, unlike Bcl-2, Mcl-1, and Bcl-xL sequestered Bak preventing it from activation through a direct interaction. Thus, when abundantly expressed, Bcl-xL can substitute for the loss of Mcl-1 whereas Bcl-2, incapable of forming a high affinity complex with Bak, could not.

• Authors: Justine Rudner, Simon J Elsaesser, Verena Jendrossek, Stephan M Huber
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 81 Issue 1 Pg. 32-42 (Jan 01 2011) ISSN: 1873-2968 [Electronic] England
• PMID: 20836993 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Elsevier Inc. All rights reserved.

Chemical References

• BCL2L1 protein, human
• Cyclooxygenase 2 Inhibitors
• Myeloid Cell Leukemia Sequence 1 Protein
• NR4A1 protein, human
• Nuclear Receptor Subfamily 4, Group A, Member 1
• Proto-Oncogene Proteins c-bcl-2
• Pyrazoles
• Sulfonamides
• bcl-2 Homologous Antagonist-Killer Protein
• bcl-X Protein
• Celecoxib

Topics

• Apoptosis (drug effects)
• Celecoxib
• Cyclooxygenase 2 Inhibitors (pharmacology)
• Gene Expression Regulation
• Humans
• Jurkat Cells
• Myeloid Cell Leukemia Sequence 1 Protein
• Nuclear Receptor Subfamily 4, Group A, Member 1 (genetics, metabolism)
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• Pyrazoles (pharmacology)
• Sulfonamides (pharmacology)
• bcl-2 Homologous Antagonist-Killer Protein (genetics, metabolism)
• bcl-X Protein (genetics, metabolism)