Title:Peroxisome Proliferator Activated Receptor α Ligands as Anticancer Drugs Targeting Mitochondrial Metabolism
Volume: 14
Issue: 3
Author(s): Maja Grabacka, Malgorzata Pierzchalska and Krzysztof Reiss
Affiliation:
Keywords:
AMP-dependent protein kinase, calorie restriction, fatty acid oxidation, glutaminolysis, ketogenesis, SIRT1, Peroxisome Proliferator, supplementary anticancer pharmacotherapy, glycolysis, fatty acid synthesis
Abstract: Tumor cells show metabolic features distinctive from normal tissues, with characteristically enhanced aerobic
glycolysis, glutaminolysis and lipid synthesis. Peroxisome proliferator activated receptor α (PPAR α) is activated by nutrients
(fatty acids and their derivatives) and influences these metabolic pathways acting antagonistically to oncogenic Akt
and c-Myc. Therefore PPAR α can be regarded as a candidate target molecule in supplementary anticancer pharmacotherapy
as well as dietary therapeutic approach. This idea is based on hitting the cancer cell metabolic weak points through
PPAR α mediated stimulation of mitochondrial fatty acid oxidation and ketogenesis with simultaneous reduction of glucose
and glutamine consumption. PPAR α activity is induced by fasting and its molecular consequences overlap with the
effects of calorie restriction and ketogenic diet (CRKD). CRKD induces increase of NAD+/NADH ratio and drop in
ATP/AMP ratio. The first one is the main stimulus for enhanced protein deacetylase SIRT1 activity; the second one activates
AMP-dependent protein kinase (AMPK). Both SIRT1 and AMPK exert their major metabolic activities such as fatty
acid oxidation and block of glycolysis and protein, nucleotide and fatty acid synthesis through the effector protein peroxisome
proliferator activated receptor gamma 1 α coactivator (PGC-1α). PGC-1α cooperates with PPAR α and their activities
might contribute to potential anticancer effects of CRKD, which were reported for various brain tumors. Therefore,
PPAR α activation can engage molecular interplay among SIRT1, AMPK, and PGC-1α that provides a new, low toxicity
dietary approach supplementing traditional anticancer regimen.
