Celecoxib promotes c-FLIP degradation through Akt-independent inhibition of GSK3

Shuzhen Chen, Wei Cao, Ping Yue, Chunhai Hao, Fadlo R. Khuri, Shi Yong Sun

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Celecoxib is a COX-2 inhibitor that reduces the risk of colon cancer. However, the basis for its cancer chemopreventive activity is not fully understood. In this study, we defined a mechanism of celecoxib action based on degradation of cellular FLICE-inhibitory protein (c-FLIP), a major regulator of the death receptor pathway of apoptosis. c-FLIP protein levels are regulated by ubiquitination and proteasome-mediated degradation. We found that celecoxib controlled c-FLIP ubiquitination through Akt-independent inhibition of glycogen synthase kinase-3 (GSK3), itself a candidate therapeutic target of interest in colon cancer. Celecoxib increased the levels of phosphorylated GSK3, including the α and β forms, even in cell lines, where phosphorylated Akt levels were not increased. Phosphoinositide 3-kinase inhibitors abrogated Akt phosphorylation as expected but had no effect on celecoxib-induced GSK3 phosphorylation. In contrast, protein kinase C (PKC) inhibitors abolished celecoxib-induced GSK3 phosphorylation, implying that celecoxib influenced GSK3 phosphorylation through a mechanism that relied upon PKC and not Akt. GSK3 blockade either by siRNA or kinase inhibitors was sufficient to attenuate c-FLIP levels. Combining celecoxib with GSK3 inhibition enhanced attenuation of c-FLIP and increased apoptosis. Proteasome inhibitor MG132 reversed the effects of GSK3 inhibition and increased c-FLIP ubiquitination, confirming that c-FLIP attenuation was mediated by proteasomal turnover as expected. Our findings reveal a novel mechanism through which the regulatory effects of c-FLIP on death receptor signaling are controlled by GSK3, which celecoxib acts at an upstream level to control independently of Akt.

Original languageEnglish (US)
Pages (from-to)6270-6281
Number of pages12
JournalCancer Research
Volume71
Issue number19
DOIs
StatePublished - Oct 1 2011
Externally publishedYes

Fingerprint

Celecoxib
CASP8 and FADD-Like Apoptosis Regulating Protein
Glycogen Synthase Kinase 3
Proteolysis
Ubiquitination
Phosphorylation
Death Domain Receptors
Colonic Neoplasms
Protein Kinase C
Apoptosis
Proteasome Inhibitors
1-Phosphatidylinositol 4-Kinase
Protein C Inhibitor
Cyclooxygenase 2 Inhibitors
Proteasome Endopeptidase Complex
Protein Kinase Inhibitors

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Celecoxib promotes c-FLIP degradation through Akt-independent inhibition of GSK3. / Chen, Shuzhen; Cao, Wei; Yue, Ping; Hao, Chunhai; Khuri, Fadlo R.; Sun, Shi Yong.

In: Cancer Research, Vol. 71, No. 19, 01.10.2011, p. 6270-6281.

Research output: Contribution to journalArticle

Chen, Shuzhen ; Cao, Wei ; Yue, Ping ; Hao, Chunhai ; Khuri, Fadlo R. ; Sun, Shi Yong. / Celecoxib promotes c-FLIP degradation through Akt-independent inhibition of GSK3. In: Cancer Research. 2011 ; Vol. 71, No. 19. pp. 6270-6281.
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