Peroxisome Proliferator Activated Receptor A Ligands as Anticancer Drugs Targeting Mitochondrial Metabolism

Maja Grabacka , Małgorzata Pierzchalska , Krzysztof Reiss

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
Author Maja Grabacka (FoFT / DoFB)
Maja Grabacka,,
- Department of Food Biotechnology
, Małgorzata Pierzchalska (FoFT / DoFB)
Małgorzata Pierzchalska,,
- Department of Food Biotechnology
, Krzysztof Reiss
Krzysztof Reiss,,
-
Journal seriesCurrent Pharmaceutical Biotechnology, ISSN 1389-2010, (A 25 pkt)
Issue year2013
Vol14
No3
Pages342-356
Publication size in sheets0.7
Keywords in English AMP-dependent protein kinase, calorie restriction, fatty acid oxidation, glutaminolysis, ketogenesis, SIRT1
URL http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3631438/
Internal identifierWTŻ/2013/53
Languageen angielski
Score (nominal)30
ScoreMinisterial score = 30.0, 26-07-2017, ArticleFromJournal
Ministerial score (2013-2016) = 30.0, 26-07-2017, ArticleFromJournal
Publication indicators WoS Citations = 27
Citation count*20 (2016-05-09)
Additional fields
FinansowanieThe authors are supported by the Polish Ministry of Science and Higher Education (grant no. N N302 130834 to M. P.) and the US National Institutes of Health (grant no. RO1 CA 095518 to K. R.)
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* presented citation count is obtained through Internet information analysis and it is close to the number calculated by the Publish or Perish system.
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