Cyclooxygenase (COX)-2 participates in various physiological functions and involves in tumorigenesis. Although transactivation of COX-2 has been well studied, the factor that responsible for COX-2 degradation remains mostly unknown. In this study, COX-2 degradation induced by caveolin-1 (Cav-1) is demonstrated by upregulated endogenous and bacteria induced COX-2 in lung and colon of caveolin-1 null mice. Ectopic expression of caveolin-1 in HT-29 cells resulted in suppressed endogenous and IL-1β induced COX-2 expression. Cav-1-induced COX-2 degradation was implicated to enhanced protein degradation by the ubiquitin-proteosome pathway. Via immunoprecipitation, we identified valosin-containing protein (VCP/p97) as the chaperon protein which interacts with both Cav-1 and COX-2 and specifically mediates COX-2, but not COX-1, degradation. Suppression of VCP via siRNA resulted in increased COX-2 level with prolonged half-life. Moreover, deletion of the COX-2 C-terminal 32 amino acids upregulated its expression level and lengthened its half-life. These data reveal a novel degradation mechanism that Cav-1 and VCP synergistically orchestrate COX-2 degradation, suggesting a role of Cav-1 in anti-tumorigenesis.
