Abstract
Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor superfamily. Originally described as “orphan nuclear receptors”, they can bind both natural and synthetic ligands acting as agonists or antagonists. In humans three subtypes, PPARα, β/δ, γ, are encoded by different genes, show tissue-specific expression patterns, and contribute to the regulation of lipid and carbohydrate metabolisms, of different cell functions, including proliferation, death, differentiation, and of processes, as inflammation, angiogenesis, immune response. The PPAR ability in increasing the expression of various antioxidant genes and decreasing the synthesis of pro-inflammatory mediators, makes them be considered among the most important regulators of the cellular response to oxidative stress conditions. Based on the multiplicity of physiological effects, PPAR involvement in cancer development and progression has attracted great scientific interest with the aim to describe changes occurring in their expression in cancer cells, and to investigate the correlation with some characteristics of cancer phenotype, including increased proliferation, decreased susceptibility to apoptosis, malignancy degree and onset of resistance to anticancer drugs. This review focuses on mechanisms underlying the antioxidant and anti-inflammatory properties of PPARs in physiological conditions, and on the reported beneficial effects of PPAR activation in cancer.
Highlights
The maintenance of intracellular redox homeostasis is crucial to ensure functionality and survival of normal cells
This review focuses on the mechanisms regulating Peroxisome proliferator-activated receptors (PPARs) expression and activity in normal cells, paying particular attention on their involvement in controlling oxidative stress and inflammation
The moderate increase of Nrf2 level was associated with the increase of PPARγ and sensibility to cytotoxic effect of arsenic trioxide (As(2)O(3)), etoposide, and doxorubicin. Another beneficial effect of PPARγ/Nrf2 activation in cancer cells has been reported in a rat model of paclitaxel-induced neuropathic pain Rosiglitazone has been shown to revert the downregulation of PPARγ occurring in the spinal cord of rats showing paclitaxel-induced neuropathic pain, and reduce the pain, probably through the increased expression of Nrf2/heme oxygenase (HO)-1 [103]. Starting from their classification as members of Nuclear Receptor superfamily, PPARs have been the subject of increasing scientific interest and studies leading to the characterisation of the roles played by the three isoforms in modulating different cell metabolisms and functions in normal cells
Summary
The maintenance of intracellular redox homeostasis is crucial to ensure functionality and survival of normal cells. Antioxidant defenses include several enzymes and molecules responsible for the cellular response to oxidative stress. The expression of several of these molecules is directly or indirectly regulated by transcription factors, including Peroxisome. In this view, PPAR antioxidant properties have been deeply investigated in both physiological and pathological conditions. This review focuses on the mechanisms regulating PPAR expression and activity in normal cells, paying particular attention on their involvement in controlling oxidative stress and inflammation. Knowledge on the effects of PPAR-mediated modulation of oxidative stress in cancer development and progression is summarized
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