Celecoxib activates Stat5 and restores or increases the expression of growth hormone-regulated genes in hepatocarcinogenesis

Abstract

We have previously evaluated the chemopreventive effect of celecoxib on preneoplastic lesions in rat liver. However, though the effects of celecoxib have been tested in a variety of carcinomas, there has not been a study on the modulation of gene expression in response to this drug. Here, we evaluated the effect of celecoxib on the gene expression profile associated with hepatocarcinogenesis. Male Sprague-Dawley rats underwent the modified resistant hepatocyte model and were fed a diet containing 1500 ppm of celecoxib. Gene expression profiles were evaluated using DNA microarrays and further validations were performed using quantitative PCR, western blotting and immunohistochemical staining. Celecoxib modulated the expression of 46 genes, and those regulated by growth hormone were selected for further analysis. Celecoxib significantly upregulated the expression of the Cyp2b1/2, Cyp3a1, and alpha2-urinary globulin (alpha2uG) genes and restored the expression of Cyp2b3 to normal. The protein expression of Cyp2b1/2 was increased, but the expressions of Cyp3a1 and alpha2uG were only restored to normal levels. The increased Cyp2b1/2 expression in response to celecoxib was mainly confined to preneoplastic lesions. A search for the upstream mediator of these genetic alterations found that carcinogenesis inactivated by 87% the signal transducer and activator of transcription 5 (Stat5), a transcription factor that is activated by growth hormone signaling, but celecoxib treatment restored its activation. In conclusion, these results suggest that celecoxib exerts anticancer effects on altered hepatic cells by restoring mRNA and the protein expression levels of specific genes, in part through the reactivation of Stat5.

The interplay between GRP78 expression and Akt activation in human colon cancer cells under celecoxib treatment

“…Several studies have indicated the potential anticarcinogenic effects of celecoxib on several types of malignancies [32,33]. Furthermore, in contrast to traditional NSAID, celecoxib leads to fewer gastrointestinal side effects [31].…”

Cancer Prevention Mediated by Caffeic Acid Phenethyl Ester Involves Cyp2b1/2 Modulation in Hepatocarcinogenesis

“…In these cases, CYP2B isoforms promote cancer, which is consistent with the results observed in our work. CYP2B1/2 is related to the detoxification of the metabolite derivatives, which are mediated by DEN activation, and decreased proliferation of precancerous cells in the liver cancer model (Arellanes-Robledo et al 2010;Salcido-Neyoy et al 2009). With other animal models such as the LEC rat, which is a mutant strain that displays hereditary hepatitis with severe jaundice and liver cancer, a decrease in CYP2B1/2 protein correlates to disease progression.…”

The Chemopreventive Capacity of Quercetin to Induce Programmed Cell Death in Hepatocarcinogenesis

“…In the MRHM, celecoxib (Marquez-Rosado et al 2005), an anti-inflammatory agent, and CAPE (Carrasco-Legleu et al 2004), an antioxidant and anti-inflammatory agent, prevent the upregulation of NFkB. There are several rat studies that have shown that antioxidant substances such as caffeic acid, phenethyl ester, and anti-inflammatory agents such as Celecoxib prevent or reverse cancer development (Beltran-Ramirez et al 2008;Arellanes-Robledo et al 2009). This current study demonstrates increased apoptosis in DEN injured cells at 24 hr after initiation and further correlates these early changes with the effect on numbers of initiated cells at 24 days.…”