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Inhibition of COX-2 in Colon Cancer Cell Lines by Celecoxib Increases the Nuclear Localization of Active p53¹

Chemoprevention Program, Institute For Cancer Prevention, American Health Foundation Cancer Center, Valhalla, New York 10595

Inactivation of the p53 tumor suppressor gene usually involves somatic mutation or binding of viral oncoproteins to the p53 protein. However, several types of malignant and premalignant tissues harbor a genetically wild-type, but transcriptionally inactive, form of p53, often localized in the cytoplasm. Electrophilic prostaglandins (PGs) are known to sequester and inactivate p53 in the cytoplasm, an effect that is likely to occur when cyclooxygenase (COX)-2 levels become elevated during colon carcinogenesis. We determined the localization and expression of p53 in the presence of PGA₁ and celecoxib, a selective COX-2 inhibitor in human colon cell lines HCT-116 (wild-type p53) and HT-29 (mutant p53). In the absence of treatment, p53 protein accumulated preferentially in the nucleus in both cell lines. We observed that the total cellular levels of p53 protein increased with exposure time and concentration of PGA₁. By contrast, p21 protein levels remained unchanged as a function of time and concentration of PGA₁. In the presence of 20 µM PGA₁, p53 accumulated preferentially in the cytosol. The nuclear:cytosol ratios of p53 were 31 and 2.1 in the controls and in the presence of PGA₁ in HCT-116 cells but were 22 and 4, respectively, in HT-29 cells. Treatment with 50 µM celecoxib for 24 h did not significantly change p53 expression and localization. However, in the presence of 100 µM celecoxib, p53 levels increased in the nucleus. The nuclear:cytosol ratios were then 31 (control) and 60 (100 µM celecoxib) in HCT-116 cells and 22 (control) and 36 (100 µM celecoxib) in HT-29 cells. These results indicate that electrophilic PGs cause wild-type p53 accumulation in the cytosol where it is inactive. Inhibition of COX-2 by celecoxib appears to alleviate this effect on p53 by reducing electrophilic PG synthesis. Thus, COX-2 inhibition of electrophilic PG formation appears to protect p53 tumor suppressor function.

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