Peroxisome Proliferator-Activated Receptors and the Hallmarks of Cancer

Abstract

Peroxisome proliferator-activated receptors (PPARs) function as nuclear transcription factors upon the binding of physiological or pharmacological ligands and heterodimerization with retinoic X receptors. Physiological ligands include fatty acids and fatty-acid-derived compounds with low specificity for the different PPAR subtypes (alpha, beta/delta, and gamma). For each of the PPAR subtypes, specific pharmacological agonists and antagonists, as well as pan-agonists, are available. In agreement with their natural ligands, PPARs are mainly focused on as targets for the treatment of metabolic syndrome and its associated complications. Nevertheless, many publications are available that implicate PPARs in malignancies. In several instances, they are controversial for very similar models. Thus, to better predict the potential use of PPAR modulators for personalized medicine in therapies against malignancies, it seems necessary and timely to review the three PPARs in relation to the didactic concept of cancer hallmark capabilities. We previously described the functions of PPAR beta/delta with respect to the cancer hallmarks and reviewed the implications of all PPARs in angiogenesis. Thus, the current review updates our knowledge on PPAR beta and the hallmarks of cancer and extends the concept to PPAR alpha and PPAR gamma.

PPAR-γ Partial Agonists in Disease-Fate Decision with Special Reference to Cancer

“…PPAR-γ is frequently expressed in various cancer cells, including breast, lung, colon, lips, kidney, pancreatic and thyroid [ 32 ]. Several studies have revealed that PPAR-γ activation by its agonists imposes cell cycle arrest [ 33 ], apoptosis [ 34 ], angiogenesis [ 35 ], inhibition [ 36 ], and redifferentiation [ 37 ], which are the key molecular processes associated with the prevention of tumor growth and progression. The expression of angiogenesis-related proteins such as vascular endothelial growth factor (VEGF) and cyclooxygenase-2 as well as inflammatory mediators in the tumor microenvironment are all inhibited by PPAR-γ activation [ 38 ].…”

“…They are considered as weak activators of PPAR-γ compared with full agonists, which shows lower transactivation potential and imparts desirable effect [ 69 ]. Agonist-mediated activation of PPAR-γ has been reported to exhibit anti-inflammatory properties, growth inhibitory effects and prevent proliferation of many human cancer cell lines [ 34 , 64 ]. Likewise, the antagonist activity has also been observed to destabilize H12 and stabilize H3 and β-sheet.…”

Phenylsulfonimide PPARα Antagonists Enhance Nrf2 Activation and Promote Oxidative Stress-Induced Apoptosis/Pyroptosis in MCF7 Breast Cancer Cells

“…The close interplay between lipid oxidation, chronic inflammation, and cancer [ 16 ] oriented the researchers to also explore the antitumor activity of PPAR ligands, leading to a significant amount of literature data, sometimes reporting contrasting results. In fact, PPAR isoforms can function as tumor suppressors or inducers, depending on the biological context and the cancer type [ 17 , 18 ]. A remarkable attention has been paid to PPARα antagonists, whose activity on fatty acid metabolism could be responsible for a metabolic alteration of cancer cells, by promoting a switching from glycolysis to fatty acid oxidation [ 19 ].…”

Rosiglitazone Ameliorates Cardiac and Skeletal Muscle Dysfunction by Correction of Energetics in Huntington’s Disease

“…PPARs belong to the group of nuclear receptors that activate or repress target genes as heterodimers with retinoic X receptors (RxR). PPARs family included: PPAR alpha (PPARα), PPAR beta/delta (PPARβ/δ), and PPAR gamma (PPARγ) [ 32 ]. Different types of cells exhibited various expressions of PPARs; thus, the outcome of its activation might be different in various tissues [ 33 ].…”