Tumors fromPpar/-null mice from all treatment groups had a higher level ofIl6mRNA (2 to 20-fold) andTnfmRNA (2 to 3-fold) compared to that of similarly treated wild-type mice (Figs. samples demonstrate that these effects were due to modulation of terminal differentiation, attenuation of inflammatory signaling and induction of apoptosis, through both PPAR/-dependent and PPAR/-impartial mechanisms. Increased levels and activity of PPAR/ by nimesulide was also observed. These studies support the hypothesis that combining ligand activation of PPAR/ with inhibition of COX2 activity increases the efficacy of preventing chemically-induced skin tumorigenesis as compared to either approach alone. Keywords:peroxisome proliferator-activated receptor-/, skin cancer, nonsteroidal anti-inflammatory drugs, chemoprevention, nuclear receptor == Introduction == Cyclooxygenase (COX) signaling pathways have important functions in modulating skin carcinogenesis. COX is the central enzyme in prostanoid biosynthesis that catalyzes the conversion of arachidonic acid to prostaglandin H2,which is usually then converted to biologically active lipids such as thromboxane (TXA2), prostaglandin E2(PGE2) and prostacyclin (PGI2) by different enzymes Jun (1). There are two isoforms of COX, COX1 and COX2. While COX1 is usually constitutively expressed, COX2 is usually induced by tumor promoters, growth factors and cytokines (2). Results from experimental animal models have established a causal relationship between COX2 and skin carcinogenesis. For example, genetic disruption of both COX1 and COX2 can prevent skin tumorigenesis (3) and non-steroidal anti-inflammatory drugs (NSAIDS) that inhibit COX activity inhibit both UV-induced and chemically-induced skin carcinogenesis (47). The proliferative effects of COX2 are due primarily to increased synthesis of prostaglandins (PGs), which directly influence cell growth after binding to specific cell surface receptors, including the prostaglandin E (EP), prostaglandin F (FP) and prostaglandin I (IP) class of receptors (8,9). For example, pro-tumorigenic effect of PGE2can be mediated by the EP2 receptor (10). While PGs can mediate their biological effects through specific prostaglandin receptors like EP, STING ligand-1 FP and IP, PGs might also modulate the activities of peroxisome proliferator-activated receptors (PPAR). Three distinct isoforms, PPAR, PPAR (also referred to as PPAR or PPAR/) and PPAR exist with essential functions in the regulation of adipogenesis, lipid metabolism, cell proliferation/apoptosis, cell differentiation, inflammatory responses and carcinogenesis (1116). PPARs regulate these pathways by modulation of gene expression through direct and indirect mechanisms. PPAR/ is found at very high levels in the nucleus of epithelium including intestine and in keratinocytes (17). In the absence of ligands, nuclear STING ligand-1 PPAR/ can also be co-immunoprecipitated with its heterodimerization partner RXR, suggesting that PPAR/ has an important constitutive role in the epithelium (17). Thus, it is not surprising that important functions for PPAR/ have been observed in skin. For example,Ppar/-null mice exhibit enhanced epidermal hyperplasia in response to phorbol ester treatment (18,19) and exacerbated chemically-induced skin tumorigenesis in a two stage carcinogen bioassay as compared to wild-type mice (20), suggesting that PPAR/ inhibits epidermal cell proliferation in response to stimuli. Consistent with this idea, PPAR/-dependent inhibition of skin tumorigenesis is found after topical application of the PPAR/ STING ligand-1 ligand GW0742 (21). The chemopreventive effects of ligand activation of PPAR/ are mediated in part by induction of unidentified target genes or non-transcriptional events that modulate terminal differentiation and inhibit cell proliferation and/or inhibition of pro-inflammatory signaling (reviewed in (11,14,15)). Some reports suggest that NSAIDs attenuates carcinogenesis by inhibiting PPAR/ expression and/or activities although this view has yet to be experimentally confirmed and there are numerous inconsistencies with this hypothesis in the literature (reviewed in (14,15)). For example, the hypothesis that NSAIDs inhibit cancer by decreasing PPAR/ expression/function is usually inconsistent with the observation that PPAR/ expression following exposure to NSAIDs is usually either unchanged or increased in human malignancy cell lines (22). Further, inhibition of chemically induced skin tumorigenesis is found in both wild-type.
Tumors fromPpar/-null mice from all treatment groups had a higher level ofIl6mRNA (2 to 20-fold) andTnfmRNA (2 to 3-fold) compared to that of similarly treated wild-type mice (Figs
