Peroxisome proliferator activated receptor α ligands as anticancer drugs targeting mitochondrial metabolism

Current Pharmaceutical Biotechnology

Volumn 14, Issue 3, 2013, Pages 342-356

  Grabacka, Maja ^a   Pierzchalska, Malgorzata ^a   Reiss, Krzysztof ^b  

^a UNIVERSITY OF AGRICULTURE IN KRAKOW   (Poland)

^b LOUISIANA STATE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

AMP dependent protein kinase; Calorie restriction; Fatty acid oxidation; Glutaminolysis; Ketogenesis; SIRT1

Indexed keywords

ACETYL COENZYME A CARBOXYLASE; CYCLIC AMP DEPENDENT PROTEIN KINASE; HIGH DENSITY LIPOPROTEIN; LOW DENSITY LIPOPROTEIN; MAMMALIAN TARGET OF RAPAMYCIN; MICRORNA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA; PROTEIN P53; PYRUVATE DEHYDROGENASE KINASE 4; REACTIVE OXYGEN METABOLITE; RETINOID X RECEPTOR; SIRTUIN; SIRTUIN 1; SOMATOMEDIN C RECEPTOR; THROMBOSPONDIN 1; TRANSCRIPTION FACTOR FKHR; TRICARBOXYLIC ACID;

ANGIOGENESIS; ANTINEOPLASTIC ACTIVITY; ARTICLE; CALORIC RESTRICTION; CANCER CELL; CELLULAR IMMUNITY; DRUG MECHANISM; FATTY ACID OXIDATION; FATTY ACID SYNTHESIS; GENE EXPRESSION; GLIOBLASTOMA; HUMAN; INTRACELLULAR SIGNALING; KETOGENESIS; KETOGENIC DIET; METABOLIC SYNDROME X; METABOLISM; MITOCHONDRIAL RESPIRATION; NONHUMAN; ONCOGENE C MYC; PROTEIN EXPRESSION; RHABDOMYOLYSIS;

AMP-ACTIVATED PROTEIN KINASES; ANIMALS; ANTINEOPLASTIC AGENTS; HUMANS; LIGANDS; MITOCHONDRIA; NEOPLASMS; PPAR ALPHA; SIRTUINS;

EID: 84875297293     PISSN: 13892010     EISSN: 18734316     Source Type: Journal    
DOI: 10.2174/1389201011314030009     Document Type: Article

References (158)

1. Desvergne, B.; Wahli, W. Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev, 1999, 20, 649-688.
2. Escher, P.; Wahli, W. Peroxisome proliferator-activated receptors: insight into multiple cellular functions. Mutat Res, 2000, 448, 121-138.
3. Glass, C. K.; Rosenfeld, M. G. The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev, 2000, 14, 121-141.
4. Blanquart, C.; Mansouri, R.; Paumelle, R.; Fruchart, J. C.; Staels, B.; Glineur, C. The protein kinase C signaling pathway regulates a molecular switch between transactivation and transrepression activity of the peroxisome proliferator-activated receptor alpha. Mol Endocrinol, 2004, 18, 1906-1918.
5. Sugden, M. C.; Caton, P. W.; Holness, M. J. PPAR control: it's SIRTainly as easy as PGC. J Endocrinol, 2010, 204, 93-104.
6. Pascual, G.; Fong, A. L.; Ogawa, S.; Gamliel, A.; Li, A. C.; Perissi, V.; Rose, D. W.; Willson, T. M.; Rosenfeld, M. G.; Glass, C. K. A SUMOylation- dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature, 2005, 437, 759-763.
7. Ghisletti, S.; Huang, W.; Ogawa, S.; Pascual, G.; Lin, M. E.; Willson, T. M.; Rosenfeld, M. G.; Glass, C. K. Parallel SUMOylationdependent pathways mediate gene- and signal-specific transrepression by LXRs and PPARgamma. Mol Cell, 2007, 25, 57-70.
8. Frederiksen, K. S.; Wulff, E. M.; Sauerberg, P.; Mogensen, J. P.; Jeppesen, L.; Fleckner, J. Prediction of PPAR-alpha ligandmediated physiological changes using gene expression profiles. J Lipid Res, 2004, 45, 592-601.
9. Ribet, C.; Montastier, E.; Valle, C.; Bezaire, V.; Mazzucotelli, A.; Mairal, A.; Viguerie, N.; Langin, D. Peroxisome proliferatoractivated receptor-alpha control of lipid and glucose metabolism in human white adipocytes. Endocrinology, 151, 123-133.
10. Muoio, D. M.; Way, J. M.; Tanner, C. J.; Winegar, D. A.; Kliewer, S. A.; Houmard, J. A.; Kraus, W. E.; Dohm, G. L. Peroxisome proliferator- activated receptor-alpha regulates fatty acid utilization in primary human skeletal muscle cells. Diabetes, 2002, 51, 901-909.
11. Luquet, S.; Lopez-Soriano, J.; Holst, D.; Fredenrich, A.; Melki, J.; Rassoulzadegan, M.; Grimaldi, P. A. Peroxisome proliferatoractivated receptor delta controls muscle development and oxidative capability. Faseb J, 2003, 17, 2299-2301.
12. Remels, A. H.; Langen, R. C.; Schrauwen, P.; Schaart, G.; Schols, A. M.; Gosker, H. R. Regulation of mitochondrial biogenesis during myogenesis. Mol Cell Endocrinol, 2010, 315, 113-120.
13. Wang, P.; Liu, J.; Li, Y.; Wu, S.; Luo, J.; Yang, H.; Subbiah, R.; Chatham, J.; Zhelyabovska, O.; Yang, Q. Peroxisome Proliferator- Activated Receptor {delta} Is an Essential Transcriptional Regulator for Mitochondrial Protection and Biogenesis in Adult Heart. Circ Res, 2010, 106, 911-919.
14. Keelan, J. A.; Sato, T. A.; Marvin, K. W.; Lander, J.; Gilmour, R. S.; Mitchell, M. D. 15-Deoxy-Delta(12,14)-prostaglandin J(2), a ligand for peroxisome proliferator-activated receptor-gamma, induces apoptosis in JEG3 choriocarcinoma cells. Biochem Biophys Res Commun, 1999, 262, 579-585.
15. Marx, N.; Sukhova, G. K.; Collins, T.; Libby, P.; Plutzky, J. PPARalpha activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells. Circulation, 1999, 99, 3125-3131.
16. Mossner, R.; Schulz, U.; Kruger, U.; Middel, P.; Schinner, S.; Fuzesi, L.; Neumann, C.; Reich, K. Agonists of peroxisome proliferator- activated receptor gamma inhibit cell growth in malignant melanoma. J Invest Dermatol, 2002, 119, 576-582.
17. Placha, W.; Gil, D.; Dembinska-Kiec, A.; Laidler, P. The effect of PPARgamma ligands on the proliferation and apoptosis of human melanoma cells. Melanoma Res, 2003, 13, 447-456.
18. Grabacka, M.; Placha, W.; Plonka, P. M.; Pajak, S.; Urbanska, K.; Laidler, P.; Slominski, A. Inhibition of melanoma metastases by fenofibrate. Arch Dermatol Res, 2004, 296, 54-58.
19. Grabacka, M.; Placha, W.; Urbanska, K.; Laidler, P.; Plonka, P. M.; Reiss, K. PPAR gamma regulates MITF and beta-catenin expression and promotes a differentiated phenotype in mouse melanoma S91. Pigment Cell Melanoma Res, 2008, 21, 388-396.
20. Grabacka, M.; Plonka, P. M.; Urbanska, K.; Reiss, K. Peroxisome proliferator-activated receptor alpha activation decreases metastatic potential of melanoma cells in vitro via down-regulation of Akt. Clin Cancer Res, 2006, 12, 3028-3036.
21. Drukala, J.; Urbanska, K.; Wilk, A.; Grabacka, M.; Wybieralska, E.; Del Valle, L.; Madeja, Z.; Reiss, K. ROS accumulation and IGF-IR inhibition contribute to fenofibrate/PPARalpha -mediated inhibition of Glioma cell notility in vitro. Mol Cancer, 2010, 9, 159.
22. Kliewer, S. A.; Sundseth, S. S.; Jones, S. A.; Brown, P. J.; Wisely, G. B.; Koble, C. S.; Devchand, P.; Wahli, W.; Willson, T. M.; Lenhard, J. M.; Lehmann, J. M. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator- activated receptors alpha and gamma. Proc Natl Acad Sci U S A, 1997, 94, 4318-4323.
23. Yu, Z.; Schneider, C.; Boeglin, W. E.; Brash, A. R. Epidermal lipoxygenase products of the hepoxilin pathway selectively activate the nuclear receptor PPARalpha. Lipids, 2007, 42, 491-497.
24. Ng, V. Y.; Huang, Y.; Reddy, L. M.; Falck, J. R.; Lin, E. T.; Kroetz, D. L. Cytochrome P450 eicosanoids are activators of peroxisome proliferator-activated receptor alpha. Drug Metab Dispos, 2007, 35, 1126-1134.
25. Muga, S. J.; Thuillier, P.; Pavone, A.; Rundhaug, J. E.; Boeglin, W. E.; Jisaka, M.; Brash, A. R.; Fischer, S. M. 8S-lipoxygenase products activate peroxisome proliferator-activated receptor alpha and induce differentiation in murine keratinocytes. Cell Growth Differ, 2000, 11, 447-454.
26. Forman, B. M.; Chen, J.; Evans, R. M. Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. Proc Natl Acad Sci U S A, 1997, 94, 4312-4317.
27. Narala, V. R.; Adapala, R. K.; Suresh, M. V.; Brock, T. G.; Peters- Golden, M.; Reddy, R. C. Leukotriene B4 is a physiologically relevant endogenous peroxisome proliferator-activated receptor- {alpha} agonist. J Biol Chem, 2010.
28. Devchand, P. R.; Keller, H.; Peters, J. M.; Vazquez, M.; Gonzalez, F. J.; Wahli, W. The PPARalpha-leukotriene B4 pathway to inflammation control. Nature, 1996, 384, 39-43.
29. Yuri, T.; Danbara, N.; Tsujita-Kyutoku, M.; Fukunaga, K.; Takada, H.; Inoue, Y.; Hada, T.; Tsubura, A. Dietary docosahexaenoic acid suppresses N-methyl-N-nitrosourea-induced mammary carcinogenesis in rats more effectively than eicosapentaenoic acid. Nutr Cancer, 2003, 45, 211-217.
30. Toriyama-Baba, H.; Iigo, M.; Asamoto, M.; Iwahori, Y.; Park, C. B.; Han, B. S.; Takasuka, N.; Kakizoe, T.; Ishikawa, C.; Yazawa, K.; Araki, E.; Tsuda, H. Organotropic chemopreventive effects of n-3 unsaturated fatty acids in a rat multi-organ carcinogenesis model. Jpn J Cancer Res, 2001, 92, 1175-1183.
31. Noguchi, M.; Minami, M.; Yagasaki, R.; Kinoshita, K.; Earashi, M.; Kitagawa, H.; Taniya, T.; Miyazaki, I. Chemoprevention of DMBA-induced mammary carcinogenesis in rats by low-dose EPA and DHA. Br J Cancer, 1997, 75, 348-353.
32. Latham, P.; Lund, E. K.; Johnson, I. T. Dietary n-3 PUFA increases the apoptotic response to 1,2-dimethylhydrazine, reduces mitosis and suppresses the induction of carcinogenesis in the rat colon. Carcinogenesis, 1999, 20, 645-650.
33. Shahidi, F.; Miraliakbari, H. Omega-3 (n-3) fatty acids in health and disease: Part 1--cardiovascular disease and cancer. J Med Food, 2004, 7, 387-401.
34. Peters, J. M.; Cheung, C.; Gonzalez, F. J. Peroxisome proliferatoractivated receptor-alpha and liver cancer: where do we stand? J Mol Med, 2005, 83, 774-785.
35. Shah, Y. M.; Morimura, K.; Yang, Q.; Tanabe, T.; Takagi, M.; Gonzalez, F. J. Peroxisome proliferator-activated receptor alpha regulates a microRNA-mediated signaling cascade responsible for hepatocellular proliferation. Mol. Cell Biol., 2007, 27, 4238-4247.
36. Gardette, V.; Bongard, V.; Dallongeville, J.; Arveiler, D.; Bingham, A.; Ruidavets, J. B.; Amouyel, P.; Haas, B.; Ducimetiere, P.; Ferrieres, J. Ten-year all-cause mortality in presumably healthy subjects on lipid-lowering drugs (from the Prospective Epidemiological Study of Myocardial Infarction [PRIME] prospective cohort). Am. J. Cardiol., 2009, 103, 381-386.
37. Demierre, M. F. What about chemoprevention for melanoma? Curr Opin Oncol, 2006, 18, 180-184.
38. Dellavalle, R. P.; Nicholas, M. K.; Schilling, L. M. Melanoma chemoprevention: a role for statins or fibrates? Am J Ther, 2003, 10, 203-210.
39. Freeman, S. R.; Drake, A. L.; Heilig, L. F.; Graber, M.; McNealy, K.; Schilling, L. M.; Dellavalle, R. P. Statins, fibrates, and melanoma risk: a systematic review and meta-analysis. J Natl Cancer Inst, 2006, 98, 1538-1546.
40. Shigeto, T.; Yokoyama, Y.; Xin, B.; Mizunuma, H. Peroxisome proliferator-activated receptor alpha and gamma ligands inhibit the growth of human ovarian cancer. Oncol Rep, 2007, 18, 833-840.
41. Yokoyama, Y.; Xin, B.; Shigeto, T.; Umemoto, M.; Kasai- Sakamoto, A.; Futagami, M.; Tsuchida, S.; Al-Mulla, F.; Mizunuma, H. Clofibric acid, a peroxisome proliferator-activated receptor alpha ligand, inhibits growth of human ovarian cancer. Mol Cancer Ther, 2007, 6, 1379-1386.
42. Tuller, E. R.; Brock, A. L.; Yu, H.; Lou, J. R.; Benbrook, D. M.; Ding, W. Q. PPARalpha signaling mediates the synergistic cytotoxicity of clioquinol and docosahexaenoic acid in human cancer cells. Biochem Pharmacol, 2009, 77, 1480-1486.
43. Saidi, S. A.; Holland, C. M.; Charnock-Jones, D. S.; Smith, S. K. In vitro and in vivo effects of the PPAR-alpha agonists fenofibrate and retinoic acid in endometrial cancer. Mol Cancer, 2006, 5, 13.
44. Zak, Z.; Gelebart, P.; Lai, R. Fenofibrate induces effective apoptosis in mantle cell lymphoma by inhibiting the TNFalpha/NFkappaB signaling axis. Leukemia.
45. Strakova, N.; Ehrmann, J.; Bartos, J.; Malikova, J.; Dolezel, J.; Kolar, Z. Peroxisome proliferator-activated receptors (PPAR) agonists affect cell viability, apoptosis and expression of cell cycle related proteins in cell lines of glial brain tumors. Neoplasma, 2005, 52, 126-136.
46. Urbanska, K.; Pannizzo, P.; Grabacka, M.; Croul, S.; Del Valle, L.; Khalili, K.; Reiss, K. Activation of PPARalpha inhibits IGF-Imediated growth and survival responses in medulloblastoma cell lines. Int J Cancer, 2008, 123, 1015-1024.
47. Wu, J.; Song, Y.; Li, H.; Chen, J. Rhabdomyolysis associated with fibrate therapy: review of 76 published cases and a new case report. Eur J Clin Pharmacol, 2009, 65, 1169-1174.
48. Maiguma, T.; Fujisaki, K.; Itoh, Y.; Makino, K.; Teshima, D.; Takahashi-Yanaga, F.; Sasaguri, T.; Oishi, R. Cell-specific toxicity of fibrates in human embryonal rhabdomyosarcoma cells. Naunyn Schmiedebergs Arch Pharmacol, 2003, 367, 289-296.
49. Kaipainen, A.; Kieran, M. W.; Huang, S.; Butterfield, C.; Bielenberg, D.; Mostoslavsky, G.; Mulligan, R.; Folkman, J.; Panigrahy, D. PPARalpha deficiency in inflammatory cells suppresses tumor growth. PLoS ONE, 2007, 2, e260.
50. Panigrahy, D.; Kaipainen, A.; Huang, S.; Butterfield, C. E.; Barnes, C. M.; Fannon, M.; Laforme, A. M.; Chaponis, D. M.; Folkman, J.; Kieran, M. W. PPARalpha agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition. Proc Natl Acad Sci U S A, 2008, 105, 985-990.
51. Chmurzynska, A. Fetal programming: link between early nutrition, DNA methylation, and complex diseases. Nutr Rev, 68, 87-98.
52. Lillycrop, K. A.; Phillips, E. S.; Jackson, A. A.; Hanson, M. A.; Burdge, G. C. Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J Nutr, 2005, 135, 1382-1386.
53. Lillycrop, K. A.; Slater-Jefferies, J. L.; Hanson, M. A.; Godfrey, K. M.; Jackson, A. A.; Burdge, G. C. Induction of altered epigenetic regulation of the hepatic glucocorticoid receptor in the offspring of rats fed a protein-restricted diet during pregnancy suggests that reduced DNA methyltransferase-1 expression is involved in impaired DNA methylation and changes in histone modifications. Br J Nutr, 2007, 97, 1064-1073.
54. Holness, M. J.; Caton, P. W.; Sugden, M. C. Acute and long-term nutrient-led modifications of gene expression: Potential role of SIRT1 as a central co-ordinator of short and longer-term programming of tissue function. Nutrition, 2010.
55. Hales, C. N.; Barker, D. J. The thrifty phenotype hypothesis. Br Med Bull, 2001, 60, 5-20.
56. Drake, A. J.; Walker, B. R. The intergenerational effects of fetal programming: non-genomic mechanisms for the inheritance of low birth weight and cardiovascular risk. J Endocrinol, 2004, 180, 1-16.
57. McMillen, I. C.; Robinson, J. S. Developmental origins of the metabolic syndrome: prediction, plasticity, and programming. Physiol. Rev., 2005, 85, 571-633.
58. Kennedy, B. K.; Steffen, K. K.; Kaeberlein, M. Ruminations on dietary restriction and aging. Cell Mol Life Sci, 2007, 64, 1323-1328.
59. Vaquero, A.; Reinberg, D. Calorie restriction and the exercise of chromatin. Genes Dev, 2009, 23, 1849-1869.
60. Hursting, S. D.; Lavigne, J. A.; Berrigan, D.; Perkins, S. N.; Barrett, J. C. Calorie restriction, aging, and cancer prevention: mechanisms of action and applicability to humans. Annu Rev Med, 2003, 54, 131-152.
61. Moore, T.; Beltran, L.; Carbajal, S.; Strom, S.; Traag, J.; Hursting, S. D.; DiGiovanni, J. Dietary energy balance modulates signaling through the Akt/mammalian target of rapamycin pathways in multiple epithelial tissues. Cancer Prev Res (Phila Pa), 2008, 1, 65-76.
62. Kenyon, C.; Chang, J.; Gensch, E.; Rudner, A.; Tabtiang, R. A C. elegans mutant that lives twice as long as wild type. Nature, 1993, 366, 461-464.
63. Yang, T.; Fu, M.; Pestell, R.; Sauve, A. A. SIRT1 and endocrine signaling. Trends Endocrinol Metab, 2006, 17, 186-191.
64. Canto, C.; Gerhart-Hines, Z.; Feige, J. N.; Lagouge, M.; Noriega, L.; Milne, J. C.; Elliott, P. J.; Puigserver, P.; Auwerx, J. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature, 2009, 458, 1056-1060.
65. Shackelford, D. B.; Shaw, R. J. The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer, 2009, 9, 563-575.
66. Carling, D.; Zammit, V. A.; Hardie, D. G. A common bicyclic protein kinase cascade inactivates the regulatory enzymes of fatty acid and cholesterol biosynthesis. FEBS Lett, 1987, 223, 217-222.
67. Marsin, A. S.; Bertrand, L.; Rider, M. H.; Deprez, J.; Beauloye, C.; Vincent, M. F.; Van den Berghe, G.; Carling, D.; Hue, L. Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia. Curr Biol, 2000, 10, 1247-1255.
68. Almeida, A.; Moncada, S.; Bolanos, J. P. Nitric oxide switches on glycolysis through the AMP protein kinase and 6-phosphofructo-2- kinase pathway. Nat Cell Biol, 2004, 6, 45-51.
69. Motawi, T. M.; Hashem, R. M.; Rashed, L. A.; El-Razek, S. M. Comparative study between the effect of the peroxisome proliferator activated receptor-alpha ligands fenofibrate and n-3 polyunsaturated fatty acids on activation of 5'-AMP-activated protein kinase-alpha1 in high-fat fed rats. J Pharm Pharmacol, 2009, 61, 1339-1346.
70. Suchankova, G.; Tekle, M.; Saha, A. K.; Ruderman, N. B.; Clarke, S. D.; Gettys, T. W. Dietary polyunsaturated fatty acids enhance hepatic AMP-activated protein kinase activity in rats. Biochem Biophys Res Commun, 2005, 326, 851-858.
71. Lee, W. J.; Kim, M.; Park, H. S.; Kim, H. S.; Jeon, M. J.; Oh, K. S.; Koh, E. H.; Won, J. C.; Kim, M. S.; Oh, G. T.; Yoon, M.; Lee, K. U.; Park, J. Y. AMPK activation increases fatty acid oxidation in skeletal muscle by activating PPARalpha and PGC-1. Biochem Biophys Res Commun, 2006, 340, 291-295.
72. Blander, G.; Guarente, L. The Sir2 family of protein deacetylases. Annu Rev Biochem, 2004, 73, 417-435.
73. Yu, J.; Auwerx, J. The role of sirtuins in the control of metabolic homeostasis. Ann N Y Acad Sci, 2009, 1173 Suppl 1, E10-19.
74. Steinkraus, K. A.; Kaeberlein, M.; Kennedy, B. K. Replicative aging in yeast: the means to the end. Annu Rev Cell Dev Biol, 2008, 24, 29-54.
75. Guarente, L. Sir2 links chromatin silencing, metabolism, and aging. Genes Dev, 2000, 14, 1021-1026.
76. Luo, J.; Li, M.; Tang, Y.; Laszkowska, M.; Roeder, R. G.; Gu, W. Acetylation of p53 augments its site-specific DNA binding both in vitro and in vivo. Proc Natl Acad Sci U S A, 2004, 101, 2259-2264.
77. Lim, C. S. SIRT1: tumor promoter or tumor suppressor? Med Hypotheses, 2006, 67, 341-344.
78. Deng, C. X. SIRT1, is it a tumor promoter or tumor suppressor? Int J Biol Sci, 2009, 5, 147-152.
79. Inoue, T.; Hiratsuka, M.; Osaki, M.; Yamada, H.; Kishimoto, I.; Yamaguchi, S.; Nakano, S.; Katoh, M.; Ito, H.; Oshimura, M. SIRT2, a tubulin deacetylase, acts to block the entry to chromosome condensation in response to mitotic stress. Oncogene, 2007, 26, 945-957.
80. Hiratsuka, M.; Inoue, T.; Toda, T.; Kimura, N.; Shirayoshi, Y.; Kamitani, H.; Watanabe, T.; Ohama, E.; Tahimic, C. G.; Kurimasa, A.; Oshimura, M. Proteomics-based identification of differentially expressed genes in human gliomas: down-regulation of SIRT2 gene. Biochem Biophys Res Commun, 2003, 309, 558-566.
81. Allison, S. J.; Milner, J. SIRT3 is pro-apoptotic and participates in distinct basal apoptotic pathways. Cell Cycle, 2007, 6, 2669-2677.
82. Lennerz, V.; Fatho, M.; Gentilini, C.; Frye, R. A.; Lifke, A.; Ferel, D.; Wolfel, C.; Huber, C.; Wolfel, T. The response of autologous T cells to a human melanoma is dominated by mutated neoantigens. Proc Natl Acad Sci U S A, 2005, 102, 16013-16018.
83. Ma, W.; Stafford, L. J.; Li, D.; Luo, J.; Li, X.; Ning, G.; Liu, M. GCIP/CCNDBP1, a helix-loop-helix protein, suppresses tumorigenesis. J Cell Biochem, 2007, 100, 1376-1386.
84. Kawahara, T. L.; Michishita, E.; Adler, A. S.; Damian, M.; Berber, E.; Lin, M.; McCord, R. A.; Ongaigui, K. C.; Boxer, L. D.; Chang, H. Y.; Chua, K. F. SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span. Cell, 2009, 136, 62-74.
85. Shulga, N.; Wilson-Smith, R.; Pastorino, J. G. Sirtuin-3 deacetylation of cyclophilin D induces dissociation of hexokinase II from the mitochondria. J Cell Sci, 2010, 123, 894-902.
86. Tsujimoto, Y.; Shimizu, S. Role of the mitochondrial membrane permeability transition in cell death. Apoptosis, 2007, 12, 835-840.
87. Pedersen, P. L. Voltage dependent anion channels (VDACs): a brief introduction with a focus on the outer mitochondrial compartment's roles together with hexokinase-2 in the Warburg effect in cancer. J Bioenerg Biomembr, 2008, 40, 123-126.
88. Sundaresan, N. R.; Samant, S. A.; Pillai, V. B.; Rajamohan, S. B.; Gupta, M. P. SIRT3 is a stress-responsive deacetylase in cardiomyocytes that protects cells from stress-mediated cell death by deacetylation of Ku70. Mol Cell Biol, 2008, 28, 6384-6401.
89. Hirschey, M. D.; Shimazu, T.; Goetzman, E.; Jing, E.; Schwer, B.; Lombard, D. B.; Grueter, C. A.; Harris, C.; Biddinger, S.; Ilkayeva, O. R.; Stevens, R. D.; Li, Y.; Saha, A. K.; Ruderman, N. B.; Bain, J. R.; Newgard, C. B.; Farese, R. V., Jr.; Alt, F. W.; Kahn, C. R.; Verdin, E. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature, 2010, 464, 121-125.
90. Hallows, W. C.; Lee, S.; Denu, J. M. Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases. Proc Natl Acad Sci U S A, 2006, 103, 10230-10235.
91. Schlicker, C.; Gertz, M.; Papatheodorou, P.; Kachholz, B.; Becker, C. F.; Steegborn, C. Substrates and regulation mechanisms for the human mitochondrial sirtuins Sirt3 and Sirt5. J Mol Biol, 2008, 382, 790-801.
92. Haigis, M. C.; Mostoslavsky, R.; Haigis, K. M.; Fahie, K.; Christodoulou, D. C.; Murphy, A. J.; Valenzuela, D. M.; Yancopoulos, G. D.; Karow, M.; Blander, G.; Wolberger, C.; Prolla, T. A.; Weindruch, R.; Alt, F. W.; Guarente, L. SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell, 2006, 126, 941-954.
93. DeBerardinis, R. J.; Lum, J. J.; Hatzivassiliou, G.; Thompson, C. B. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab, 2008, 7, 11-20.
94. Kroemer, G.; Pouyssegur, J. Tumor cell metabolism: cancer's Achilles' heel. Cancer Cell, 2008, 13, 472-482.
95. Young, C. D.; Anderson, S. M. Sugar and fat - that's where it's at: metabolic changes in tumors. Breast Cancer Res, 2008, 10, 202.
96. Weinberg, F.; Chandel, N. S. Mitochondrial metabolism and cancer. Ann N Y Acad Sci, 2009, 1177, 66-73.
97. Wise, D. R.; DeBerardinis, R. J.; Mancuso, A.; Sayed, N.; Zhang, X. Y.; Pfeiffer, H. K.; Nissim, I.; Daikhin, E.; Yudkoff, M.; McMahon, S. B.; Thompson, C. B. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci U S A, 2008, 105, 18782-18787.
98. Gao, P.; Tchernyshyov, I.; Chang, T. C.; Lee, Y. S.; Kita, K.; Ochi, T.; Zeller, K. I.; De Marzo, A. M.; Van Eyk, J. E.; Mendell, J. T.; Dang, C. V. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature, 2009, 458, 762-765.
99. Yang, C.; Sudderth, J.; Dang, T.; Bachoo, R. M.; McDonald, J. G.; DeBerardinis, R. J. Glioblastoma cells require glutamate dehydrogenase to survive impairments of glucose metabolism or Akt signaling. Cancer Res, 2009, 69, 7986-7993.
100. Ortega, A. D.; Sanchez-Arago, M.; Giner-Sanchez, D.; Sanchez- Cenizo, L.; Willers, I.; Cuezva, J. M. Glucose avidity of carcinomas. Cancer Lett, 2009, 276, 125-135.
101. Pelicano, H.; Xu, R. H.; Du, M.; Feng, L.; Sasaki, R.; Carew, J. S.; Hu, Y.; Ramdas, L.; Hu, L.; Keating, M. J.; Zhang, W.; Plunkett, W.; Huang, P. Mitochondrial respiration defects in cancer cells cause activation of Akt survival pathway through a redox-mediated mechanism. J Cell Biol, 2006, 175, 913-923.
102. Moreno-Sanchez, R.; Rodriguez-Enriquez, S.; Marin-Hernandez, A.; Saavedra, E. Energy metabolism in tumor cells. Febs J, 2007, 274, 1393-1418.
103. Deberardinis, R. J.; Sayed, N.; Ditsworth, D.; Thompson, C. B. Brick by brick: metabolism and tumor cell growth. Curr Opin Genet Dev, 2008, 18, 54-61.
104. Rathmell, J. C.; Fox, C. J.; Plas, D. R.; Hammerman, P. S.; Cinalli, R. M.; Thompson, C. B. Akt-directed glucose metabolism can prevent Bax conformation change and promote growth factorindependent survival. Mol Cell Biol, 2003, 23, 7315-7328.
105. Robey, R. B.; Hay, N. Mitochondrial hexokinases: guardians of the mitochondria. Cell Cycle, 2005, 4, 654-658.
106. Elstrom, R. L.; Bauer, D. E.; Buzzai, M.; Karnauskas, R.; Harris, M. H.; Plas, D. R.; Zhuang, H.; Cinalli, R. M.; Alavi, A.; Rudin, C. M.; Thompson, C. B. Akt stimulates aerobic glycolysis in cancer cells. Cancer Res, 2004, 64, 3892-3899.
107. Plas, D. R.; Thompson, C. B. Akt-dependent transformation: there is more to growth than just surviving. Oncogene, 2005, 24, 7435-7442.
108. Porstmann, T.; Griffiths, B.; Chung, Y. L.; Delpuech, O.; Griffiths, J. R.; Downward, J.; Schulze, A. PKB/Akt induces transcription of enzymes involved in cholesterol and fatty acid biosynthesis via activation of SREBP. Oncogene, 2005, 24, 6465-6481.
109. Shim, H.; Dolde, C.; Lewis, B. C.; Wu, C. S.; Dang, G.; Jungmann, R. A.; Dalla-Favera, R.; Dang, C. V. c-Myc transactivation of LDH-A: implications for tumor metabolism and growth. Proc Natl Acad Sci U S A, 1997, 94, 6658-6663.
110. Kim, J. W.; Zeller, K. I.; Wang, Y.; Jegga, A. G.; Aronow, B. J.; O'Donnell, K. A.; Dang, C. V. Evaluation of myc E-box phylogenetic footprints in glycolytic genes by chromatin immunoprecipitation assays. Mol Cell Biol, 2004, 24, 5923-5936.
111. Dang, C. V.; Le, A.; Gao, P. MYC-induced cancer cell energy metabolism and therapeutic opportunities. Clin Cancer Res, 2009, 15, 6479-6483.
112. Sanchez-Arago, M.; Chamorro, M.; Cuezva, J. M. Selection of cancer cells with repressed mitochondria triggers colon cancer progression. Carcinogenesis, 2010.
113. Grabacka, M.; Reiss, K. Anticancer Properties of PPARalpha- Effects on Cellular Metabolism and Inflammation. PPAR Res, 2008, 2008, 930705.
114. Finck, B. N.; Kelly, D. P. Peroxisome proliferator-activated receptor alpha (PPARalpha) signaling in the gene regulatory control of energy metabolism in the normal and diseased heart. J Mol Cell Cardiol, 2002, 34, 1249-1257.
115. Oosterveer, M. H.; Grefhorst, A.; van Dijk, T. H.; Havinga, R.; Staels, B.; Kuipers, F.; Groen, A. K.; Reijngoud, D. J. Fenofibrate simultaneously induces hepatic fatty acid oxidation, synthesis, and elongation in mice. J Biol Chem, 2009, 284, 34036-34044.
116. Ahmed, W.; Ziouzenkova, O.; Brown, J.; Devchand, P.; Francis, S.; Kadakia, M.; Kanda, T.; Orasanu, G.; Sharlach, M.; Zandbergen, F.; Plutzky, J. PPARs and their metabolic modulation: new mechanisms for transcriptional regulation? J Intern Med, 2007, 262, 184-198.
117. Nakamura, M. T.; Cheon, Y.; Li, Y.; Nara, T. Y. Mechanisms of regulation of gene expression by fatty acids. Lipids, 2004, 39, 1077-1083.
118. Sugden, M. C.; Holness, M. J. Mechanisms underlying regulation of the expression and activities of the mammalian pyruvate dehydrogenase kinases. Arch Physiol Biochem, 2006, 112, 139-149.
119. Kersten, S.; Mandard, S.; Escher, P.; Gonzalez, F. J.; Tafuri, S.; Desvergne, B.; Wahli, W. The peroxisome proliferator-activated receptor alpha regulates amino acid metabolism. Faseb J, 2001, 15, 1971-1978.
120. Sheikh, K.; Camejo, G.; Lanne, B.; Halvarsson, T.; Landergren, M. R.; Oakes, N. D. Beyond lipids, pharmacological PPARalpha activation has important effects on amino acid metabolism as studied in the rat. Am J Physiol Endocrinol Metab, 2007, 292, E1157-1165.
121. Makowski, L.; Noland, R. C.; Koves, T. R.; Xing, W.; Ilkayeva, O. R.; Muehlbauer, M. J.; Stevens, R. D.; Muoio, D. M. Metabolic profiling of PPARalpha-/- mice reveals defects in carnitine and amino acid homeostasis that are partially reversed by oral carnitine supplementation. Faseb J, 2009, 23, 586-604.
122. Purushotham, A.; Schug, T. T.; Xu, Q.; Surapureddi, S.; Guo, X.; Li, X. Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab, 2009, 9, 327-338.
123. Seyfried, B. T.; Kiebish, M.; Marsh, J.; Mukherjee, P. Targeting energy metabolism in brain cancer through calorie restriction and the ketogenic diet. J Cancer Res Ther, 2009, 5 Suppl 1, S7-15.
124. Rodriguez, J. C.; Gil-Gomez, G.; Hegardt, F. G.; Haro, D. Peroxisome proliferator-activated receptor mediates induction of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene by fatty acids. J Biol Chem, 1994, 269, 18767-18772.
125. Cullingford, T. E.; Dolphin, C. T.; Sato, H. The peroxisome proliferator- activated receptor alpha-selective activator ciprofibrate upregulates expression of genes encoding fatty acid oxidation and ketogenesis enzymes in rat brain. Neuropharmacology, 2002, 42, 724-730.
126. Rebrin, I.; Kamzalov, S.; Sohal, R. S. Effects of age and caloric restriction on glutathione redox state in mice. Free Radic Biol Med, 2003, 35, 626-635.
127. Ali, M. A.; Yasui, F.; Matsugo, S.; Konishi, T. The lactatedependent enhancement of hydroxyl radical generation by the Fenton reaction. Free Radic Res, 2000, 32, 429-438.
128. Andersson, A. K.; Ronnback, L.; Hansson, E. Lactate induces tumour necrosis factor-alpha, interleukin-6 and interleukin-1beta release in microglial- and astroglial-enriched primary cultures. J Neurochem, 2005, 93, 1327-1333.
129. Zhou, W.; Mukherjee, P.; Kiebish, M. A.; Markis, W. T.; Mantis, J. G.; Seyfried, T. N. The calorically restricted ketogenic diet, an effective alternative therapy for malignant brain cancer. Nutr Metab (Lond), 2007, 4, 5.
130. Freeman, J. M.; Vining, E. P.; Pillas, D. J.; Pyzik, P. L.; Casey, J. C.; Kelly, L. M. The efficacy of the ketogenic diet-1998: a prospective evaluation of intervention in 150 children. Pediatrics, 1998, 102, 1358-1363.
131. Cullingford, T. E. The ketogenic diet; fatty acids, fatty acidactivated receptors and neurological disorders. Prostaglandins Leukot Essent Fatty Acids, 2004, 70, 253-264.
132. Wheless, J. W. History of the ketogenic diet. Epilepsia, 2008, 49 Suppl 8, 3-5.
133. Blazquez, C.; Woods, A.; de Ceballos, M. L.; Carling, D.; Guzman, M. The AMP-activated protein kinase is involved in the regulation of ketone body production by astrocytes. J Neurochem, 1999, 73, 1674-1682.
134. Blazquez, C.; Sanchez, C.; Velasco, G.; Guzman, M. Role of carnitine palmitoyltransferase I in the control of ketogenesis in primary cultures of rat astrocytes. J Neurochem, 1998, 71, 1597-1606.
135. Blazquez, C.; Sanchez, C.; Daza, A.; Galve-Roperh, I.; Guzman, M. The stimulation of ketogenesis by cannabinoids in cultured astrocytes defines carnitine palmitoyltransferase I as a new ceramideactivated enzyme. J Neurochem, 1999, 72, 1759-1768.
136. Edmond, J. Essential polyunsaturated fatty acids and the barrier to the brain: the components of a model for transport. J Mol Neurosci, 2001, 16, 181-193; discussion 215-121.
137. Konig, B.; Koch, A.; Giggel, K.; Dordschbal, B.; Eder, K.; Stangl, G. I. Monocarboxylate transporter (MCT)-1 is up-regulated by PPARalpha. Biochim Biophys Acta, 2008, 1780, 899-904.
138. Camarero, N.; Mascaro, C.; Mayordomo, C.; Vilardell, F.; Haro, D.; Marrero, P. F. Ketogenic HMGCS2 Is a c-Myc target gene expressed in differentiated cells of human colonic epithelium and down-regulated in colon cancer. Mol Cancer Res, 2006, 4, 645-653.
139. Wenz, T.; Diaz, F.; Spiegelman, B. M.; Moraes, C. T. Activation of the PPAR/PGC-1alpha pathway prevents a bioenergetic deficit and effectively improves a mitochondrial myopathy phenotype. Cell Metab, 2008, 8, 249-256.
140. Kalaany, N. Y.; Sabatini, D. M. Tumours with PI3K activation are resistant to dietary restriction. Nature, 2009, 458, 725-731.
141. Huang, H.; Tindall, D. J. Dynamic FoxO transcription factors. J Cell Sci, 2007, 120, 2479-2487.
142. Aman, M. J.; Lamkin, T. D.; Okada, H.; Kurosaki, T.; Ravichandran, K. S. The inositol phosphatase SHIP inhibits Akt/PKB activation in B cells. J Biol Chem, 1998, 273, 33922-33928.
143. Meier, R.; Thelen, M.; Hemmings, B. A. Inactivation and dephosphorylation of protein kinase Balpha (PKBalpha) promoted by hyperosmotic stress. Embo J, 1998, 17, 7294-7303.
144. Liu, Q.; Sasaki, T.; Kozieradzki, I.; Wakeham, A.; Itie, A.; Dumont, D. J.; Penninger, J. M. SHIP is a negative regulator of growth factor receptor-mediated PKB/Akt activation and myeloid cell survival. Genes Dev, 1999, 13, 786-791.
145. Ramaswamy, S.; Nakamura, N.; Vazquez, F.; Batt, D. B.; Perera, S.; Roberts, T. M.; Sellers, W. R. Regulation of G1 progression by the PTEN tumor suppressor protein is linked to inhibition of the phosphatidylinositol 3-kinase/Akt pathway. Proc Natl Acad Sci U S A, 1999, 96, 2110-2115.
146. Backman, S. A.; Stambolic, V.; Suzuki, A.; Haight, J.; Elia, A.; Pretorius, J.; Tsao, M. S.; Shannon, P.; Bolon, B.; Ivy, G. O.; Mak, T. W. Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease. Nat Genet, 2001, 29, 396-403.
147. Du, K.; Herzig, S.; Kulkarni, R. N.; Montminy, M. TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver. Science, 2003, 300, 1574-1577.
148. Koo, S. H.; Satoh, H.; Herzig, S.; Lee, C. H.; Hedrick, S.; Kulkarni, R.; Evans, R. M.; Olefsky, J.; Montminy, M. PGC-1 promotes insulin resistance in liver through PPAR-alpha-dependent induction of TRB-3. Nat Med, 2004, 10, 530-534.
149. Koh, H. J.; Arnolds, D. E.; Fujii, N.; Tran, T. T.; Rogers, M. J.; Jessen, N.; Li, Y.; Liew, C. W.; Ho, R. C.; Hirshman, M. F.; Kulkarni, R. N.; Kahn, C. R.; Goodyear, L. J. Skeletal muscle-selective knockout of LKB1 increases insulin sensitivity, improves glucose homeostasis, and decreases TRB3. Mol Cell Biol, 2006, 26, 8217-8227.
150. Selim, E.; Frkanec, J. T.; Cunard, R. Fibrates upregulate TRB3 in lymphocytes independent of PPAR alpha by augmenting CCAAT/enhancer-binding protein beta (C/EBP beta) expression. Mol Immunol, 2007, 44, 1218-1229.
151. Scatena, R.; Bottoni, P.; Giardina, B. Mitochondria, PPARs, and Cancer: Is Receptor-Independent Action of PPAR Agonists a Key? PPAR Res, 2008, 2008, 256251.
152. Nemoto, S.; Fergusson, M. M.; Finkel, T. SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1{alpha}. J Biol Chem, 2005, 280, 16456-16460.
153. Rodgers, J. T.; Lerin, C.; Haas, W.; Gygi, S. P.; Spiegelman, B. M.; Puigserver, P. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature, 2005, 434, 113-118.
154. Hou, X.; Xu, S.; Maitland-Toolan, K. A.; Sato, K.; Jiang, B.; Ido, Y.; Lan, F.; Walsh, K.; Wierzbicki, M.; Verbeuren, T. J.; Cohen, R. A.; Zang, M. SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase. J Biol Chem, 2008, 283, 20015-20026.
155. Lan, F.; Cacicedo, J. M.; Ruderman, N.; Ido, Y. SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1. Possible role in AMP-activated protein kinase activation. J Biol Chem, 2008, 283, 27628-27635.
156. Jager, S.; Handschin, C.; St-Pierre, J.; Spiegelman, B. M. AMPactivated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci U S A, 2007, 104, 12017-12022.
157. Li, X.; Monks, B.; Ge, Q.; Birnbaum, M. J. Akt/PKB regulates hepatic metabolism by directly inhibiting PGC-1alpha transcription coactivator. Nature, 2007, 447, 1012-1016.
158. Irrcher, I.; Ljubicic, V.; Hood, D. A. Interactions between ROS and AMP kinase activity in the regulation of PGC-1alpha transcription in skeletal muscle cells. Am J Physiol Cell Physiol, 2009, 296, C116-123.