PPARs and the Kynurenine Pathway in Melanoma—Potential Biological Interactions

Abstract

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors involved in various physiological and pathological processes within the skin. PPARs regulate several processes in one of the most aggressive skin cancers, melanoma, including proliferation, cell cycle, metabolic homeostasis, cell death, and metastasis. In this review, we focused not only on the biological activity of PPAR isoforms in melanoma initiation, progression, and metastasis but also on potential biological interactions between the PPAR signaling and the kynurenine pathways. The kynurenine pathway is a major pathway of tryptophan metabolism leading to nicotinamide adenine dinucleotide (NAD+) production. Importantly, various tryptophan metabolites exert biological activity toward cancer cells, including melanoma. Previous studies confirmed the functional relationship between PPAR and the kynurenine pathway in skeletal muscles. Despite the fact this interaction has not been reported in melanoma to date, some bioinformatics data and biological activity of PPAR ligands and tryptophan metabolites may suggest a potential involvement of these metabolic and signaling pathways in melanoma initiation, progression, and metastasis. Importantly, the possible relationship between the PPAR signaling pathway and the kynurenine pathway may relate not only to the direct biological effect on melanoma cells but also to the tumor microenvironment and the immune system.

Peroxisome proliferator-activated receptorα/γ agonist pioglitazone for rescuing relapsed or refractory neoplasias by unlocking phenotypic plasticity

“…Pioglitazone is a thiazolidine-2, 4-dione compound and an approved dual peroxisome proliferator-activated receptor (PPAR)α/γ agonist for the treatment of insulin resistance ( 1 , 2 ). Besides this limited indication, more and more pre-clinical data reveal a broad, multileveled activity profile in cancer tissue, modulating cancer-associated inflammation, immune response, sustained proliferative signaling, cancer metabolism, angiogenesis, i.e., tissue functions that are described by the hallmarks of cancer ( 3 , 4 ).…”