NF-kappaB/PPAR gamma and/or AP-1/PPAR gamma 'on/off' switches and induction of CBP in colon adenocarcinomas: correlation with COX-2 expression.

Background And Aims: Several studies indicate that peroxisome proliferator-activated receptor gamma (PPAR gamma) represses activator protein-1 (AP-1) and nuclear factor kappa B (NF-kappaB) transcriptional activity and this negative cross-talk occupies an important role in carcinogenesis. The present study evaluated the differential expression profile of AP-1 constituents (c-FOS and phosphorylated-active pc-JUN), p-I kappaB-alpha (phosphorylated I kappaB-alpha, a signaling intermediate of NF-kappaB pathway), PPAR gamma, cyclic AMP-response element binding-binding protein (CBP, a known AP-1, NF-kappaB, and PPAR gamma transcriptional coactivator), epidermal growth factor receptor (EGF-R), p53, and COX-2 in normal colonic epithelial cells and colon adenocarcinoma cells.

Materials And Methods: Immunohistochemical methodology was performed on formalin-fixed, paraffin-embedded sections from 60 patients with colon adenocarcinomas. A molecular profile was created for each patient and the induction or down-regulation of each pathway from normal to cancer cells was documented. Relationships between transcription factors and downstream molecular targets were evaluated by Spearman's rho correlation coefficient and validated by nonparametric Kruskal-Wallis test.

Results/findings: P-I kappaB-alpha (P<0.001), CBP (P<0.001), c-FOS (P=0.047), pc-JUN (P=0.047), and EGF-R (P<0.001) were up-regulated in colon adenocarcinomas while PPAR gamma (P<0.001) was concomitantly down-regulated. p-I kappaB-alpha, CBP, pc-JUN, EGF-R, and p53 expression all correlated positively with COX-2 while PPAR gamma expression correlated inversely with COX-2.

Interpretation/conclusion: NF-kappaB/PPAR gamma and/or AP-1/PPAR gamma expressional 'on/off' switches are common molecular events during colorectal carcinogenesis. Down-regulation of PPAR gamma and induction of the CBP transcriptional coactivator can augment NF-kappaB and AP-1 transcriptional activities leading to up-regulation of COX-2 expression in colon adenocarcinoma cells. p-I kappaB-alpha, pc-JUN, and CBP could potentially provide the basis for future molecular-targeted anticancer therapies.