Peroxisome proliferator-activated receptors (PPARs), members of the nuclear hormone receptor superfamily, function as transcription factors and modulators of gene expression. These actions allow PPARs to regulate a variety of biological processes and to play a significant role in several diseases and conditions. The current literature describes frequently opposing and paradoxical roles for the three PPAR isotypes, PPARa, PPARb/d and PPARg, in cancer. While some studies have implicated PPARs in the promotion and development of cancer, others, in contrast, have presented evidence for a protective role for these receptors against cancer. In some tissues, the expression level of these receptors and/or their activation correlates with a positive outcome against cancer, while, in other tissue types, their expression and activation have the opposite effect. These disparate findings raise the possibility of (i) PPAR receptor-independent effects, including effects on receptors other than PPARs by the utilized ligands; (ii) cancer stage-specific effect; and/or (iii) differences in essential ligand-related pharmacokinetic considerations. In this review, we highlight the latest available studies on the role of the various PPAR isotypes in cancer in several major organs and present challenges as well as promising opportunities in the field.

Peroxisome proliferator-activated receptors (PPARs) were discovered over a decade ago, and were classified as orphan members of the nuclear receptor superfamily. To date, three PPAR subtypes have been discovered and characterized (PPARα, β/δ, γ). Different PPAR subtypes have been shown to play crucial roles in important diseases and conditions such as obesity, diabetes, atherosclerosis, cancer, and fertility. Among the most studied roles of PPARs is their involvement in inflammatory processes. Numerous studies have revealed that agonists of PPARα and PPARγ exert anti-inflammatory effects both in vitro and in vivo. Using the carrageenan-induced paw edema model of inflammation, a recent study in our laboratories showed that these agonists hinder the initiation phase, but not the late phase of the inflammatory process. Furthermore, in the same experimental model, we recently also observed that activation of PPARδ exerted an anti-inflammatory effect. Despite the fact that exclusive dependence of these effects on PPARs has been questioned, the bulk of evidence suggests that all three PPAR subtypes, PPARα, δ, γ, play a significant role in controlling inflammatory responses. Whether these subtypes act via a common mechanism or are independent of each other remains to be elucidated. However, due to the intensity of research efforts in this area, it is anticipated that these efforts will result in the development of PPAR ligands as therapeutic agents for the treatment of inflammatory diseases.

Despite rising interest in the health problems of the elderly, information on senescence-related alterations in essential metabolic pathways and their responses to various chemicals is scarce. Although peroxisomal pathways are involved in a multitude of cellular fnctions, little attention has been given to the potential relationship between senescence of these organelles and the process of aging and disease. Although the prevailing experimental evidence points to a decline in liver peroxisomal enzyme activities and a muted response to peroxisome-proleratn chemicals in aged animals, it is also evident that aged animals are more susceptible, inl comparison to their young counterparts, to the hepatocarcinogenic efecs of these chemicals. Furthermore, little is known about extraperoxisomal effects of peroxisome proliferators in aged animals. This review evaluates published studies on the impat of aging on basal hepatic:peroxisomal metabolism, response to peroxisome proliferators, and changes in signal trauction pathways involved in these processes, with the aim of stimulating research efforts in this important area. The potential intricate relationship among senescent perosomes, aged hepatocytes, and health are also discussed.

Peroxisome proliferators are a structurally diverse group of compounds that include the fibrate hypolipidemic drugs, the phthalate ester industrial plasticizers, the phenoxy acid herbicides, and the anti-wetting corrosion inhibitors perfluorinated straight-chain monocarboxylic fatty acids. Administration of these chemicals to rodents results in a number of effects, the most prominent being hepatomegaly and induction of peroxisomal enzyme activities. Several of these compounds have also been associated with the production of liver tumors in rodents and are classified as nongenotoxic hepatocarcinogens. Experimental evidence suggests that humans are not susceptible to these effects following exposure to peroxisome-proliferating compounds. This has led to the proposal that an "actual threat to humans" from exposure to one of these compounds seems "rather unlikely". Indeed, recent reports suggest that peroxisome proliferators may prove valuable as antitumor agents in humans. However, this assessment is preliminary given that peroxisome proliferators also produce a myriad of extraperoxisomal effects in livers and other tissues of experimental animals. Such effects include both stimulation and inhibition of mitochondrial and microsomal metabolism and alteration of the activities of various cytosolic enzymes. These responses may be directly or indirectly related to the effects on peroxisomes or may be totally independent of these events. Whether the extraperoxisomal effects of these compounds occur in humans is not known and their potential impact on human health remains to be investigated.

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