|Department Affiliations||Department of Biological Chemistry, Sidney Kimmel Coprehensive Cancer Center.|
|SOM Address||Room 400 Biophysics Building|
In addition to studies focused on elucidating the structure, mechanism, and regulation of the mammalian mitochondrial ATP synthase, a major disease focus of the Pedersen lab for many years has been cancer because of its alterations in energy metabolism. The laboratory uses chemistry, molecular biology, biophysics, immunology, tissue culture and animal models to better understand the energetics/energy metabolism of normal and cancer cells. As indicated below, a major focus is on the two ‘power plants’, the mitochondria and the glucose catabolic system (glycolysis), as well as on the interaction between these two systems.
The mechanism and regulation of ATP synthesis in mammalian mitochondria.
This involves the study of the molecular properties of the ATP synthase complex that consists of two nano-motors both of which are necessary to make ATP. In a collaborative study we have obtained the 3-D structure of one of the motors and are now working on the structure of the whole complex that consists of 17 subunit types and over 30 total subunits. We now know that the ATP synthase is in complex formation with the transport system (carrier) for phosphate and the transport system for adenine nucleotides (ADP and ATP). We named this complex the ATP Synthasome. Recently, we have spent considerable time in an attempt to elucidate the role(s) of subunits of the ATP synthasome that are not directly involved in catalysis or transport. Although all results have not yet been obtained, those that have suggest a role of these subunits in the regulation of the ATP synthase. Also we found that the ATP synthasome contains another key protein originally thought to be within the outer membrane as well as at contact sites between inner and outer membranes. This protein is likely critical for channeling ATP to the cytoplasm.
Cancer: Regulation and targeting genes and proteins responsible for one of its most common phenotypes and developing a novel potent anticancer agent, 3-bromopyruvate (3BP).
The most common metabolic phenotype of malignant cells & tumors including those derived from liver, breast, lung, brain, etc. is their capacity to utilize glucose at high rates even in the presence of oxygen. The pivotal enzyme involved is hexokinase 2 (HK-2) that is markedly elevated and bound at or very near the outer mitochondrial membrane protein named “VDAC” (voltage dependent anion channel). At this location, hexokinase 2 not only helps couple ATP formation in mitochondria to the phosphorylation of glucose to “jump start”glucose catabolism, it also represses this organelle’s contribution to cell death. Therefore, HK-2, in addition to its critical metabolic role, also promotes cancer by helping immortalize cancer cells. This said we hope to find new agents that can specifically target and inhibit either HK-2 or its gene in cancer cells while leaving normal cell unharmed.
- Mitochondrial ATP synthase catalytic mechanism: a novel visual comparative structural approach emphasizes pivotal roles for Mg²⁺ and P-loop residues in making ATP. Blum DJ, Ko YH, Pedersen PL. Biochemistry. 2012 Feb 21;51(7):1532-46. doi: 10.1021/bi201595v. Epub 2012 Feb 9.PMID:22243519
- A translational study “case report” on the small molecule “energy blocker” 3-bromopyruvate (3BP) as a potent anticancer agent: from bench side to bedside.Ko YH, Verhoeven HA, Lee MJ, Corbin DJ, Vogl TJ, Pedersen PL.J Bioenerg Biomembr. 2012 Feb;44(1):163-70.. Epub 2012 Feb 11. PMID: 22328020
- Butyrate activates the monocarboxylate transporter MCT4 expression in breast cancer cells and enhances the antitumor activity of 3-bromopyruvate. Queirós O, Preto A, Pacheco A, Pinheiro C, Azevedo-Silva J, Moreira R, Pedro M, Ko YH, Pedersen PL, Baltazar F, Casal M. J Bioenerg Biomembr. 2012 Feb;44(1):141-53. doi: 10.1007/s10863-012-9418-3. Epub 2012 Feb 17.PMID:22350013
- Transport and cytotoxicity of the anticancer drug 3-bromopyruvate in the yeast Saccharomyces cerevisiae. Lis P, Zarzycki M, Ko YH, Casal M, Pedersen PL, Goffeau A, Ułaszewski S. J Bioenerg Biomembr. 2012 Feb;44(1):155-61. doi: 10.1007/s10863-012-9421-8. Epub 2012 Feb 23.PMID:22359102
- 3-Bromopyruvate (3BP) a fast acting, promising, powerful, specific, and effective “small molecule” anti-cancer agent taken from labside to bedside: introduction to a special issue. Pedersen PL. J Bioenerg Biomembr. 2012 Feb; 44(1):1-6. doi: 10.1007/s10863-012-9425-4. PMID: 22382780
- Mitochondria in relation to cancer metastasis: introduction to a mini-review series. Pedersen PL.J Bioenerg Biomembr. 2012 Dec;44(6):615-7. doi: 10.1007/s10863-012-9470-z.PMID:22926290
- 3-Bromopyruvate: a novel antifungal agent against the human pathogen Cryptococcus neoformans. Dyląg M, Lis P, Niedźwiecka K, Ko YH, Pedersen PL, Goffeau A, Ułaszewski S.Biochem Biophys Res Commun. 2013 May 3;434(2):322-7. doi: 10.1016/j.bbrc.2013.02.125. Epub 2013 Mar 26.PMID:23541578
- Killing multiple myeloma cells with the small molecule 3-bromopyruvate: implications for therapy.Majkowska-Skrobek G, Augustyniak D, Lis P, Bartkowiak A, Gonchar M, Ko YH, Pedersen PL, Goffeau A, Ułaszewski S. Anticancer Drugs. 2014 Jul;25(6):673-82..PMID::24557015
- The cytotoxicity of 3-bromopyruvate in breast cancer cells depends on extracellular pH. Azevedo-Silva J, Queirós O, Ribeiro A, Baltazar F, Young KH, Pedersen PL, Preto A, Casal M. Biochem J. 2015 Apr 15;467(2):247-58. doi: 10.1042/BJ20140921.PMID:25641640
- The anticancer agent 3-bromopyruvate: a simple but powerful molecule taken from the lab to the bedside. Azevedo-Silva J, Queirós O, Baltazar F, Ułaszewski S, Goffeau A, Ko YH, Pedersen PL, Preto A, Casal M. J Bioenerg Biomembr. 2016 Jul 25. [Epub ahead of print] Review. PMID:27457582
- Screening the yeast genome for energetic metabolism pathways involved in a phenotypic response to the anti-cancer agent 3-bromopyruvate. Lis P, Jurkiewicz P, Cal-Bąkowska M, Ko YH, Pedersen PL, Goffeau A, Ułaszewski S. Oncotarget. 2016 Mar 1;7(9):10153-73. doi: 10.18632/oncotarget.7174. PMID:26862728
- Human Hepatocellular Carcinoma Metabolism: Imaging by Hyperpolarized 13C Magnetic Resonance Spectroscopy.Darpolor MM, Kaplan DE, Pedersen PL, Glickson JD. J Liver Disease Transplant. 2012 Sep 1;1(1). doi: 10.4172/2325-9612.1000101. PMID:24224182
- Designing a broad-spectrum integrative approach for cancer prevention and treatment. Block KI, Gyllenhaal C, Lowe L, Amedei A, Amin AR, Amin A, Aquilano K, Arbiser J, Arreola A, Arzumanyan A, Ashraf SS, Azmi AS, Benencia F, Bhakta D, Bilsland A, Bishayee A, Blain SW, Block PB, Boosani CS, Carey TE, Carnero A, Carotenuto M, Casey SC, Chakrabarti M, Chaturvedi R, Chen GZ, Chen H, Chen S, Chen YC, Choi BK, Ciriolo MR, Coley HM, Collins AR, Connell M, Crawford S, Curran CS, Dabrosin C, Damia G, Dasgupta S, DeBerardinis RJ, Decker WK, Dhawan P, Diehl AM, Dong JT, Dou QP, Drew JE, Elkord E, El-Rayes B, Feitelson MA, Felsher DW, Ferguson LR, Fimognari C, Firestone GL, Frezza C, Fujii H, Fuster MM, Generali D, Georgakilas AG, Gieseler F, Gilbertson M, Green MF, Grue B, Guha G, Halicka D, Helferich WG, Heneberg P, Hentosh P, Hirschey MD, Hofseth LJ, Holcombe RF, Honoki K, Hsu HY, Huang GS, Jensen LD, Jiang WG, Jones LW, Karpowicz PA, Keith WN, Kerkar SP, Khan GN, Khatami M, Ko YH, Kucuk O, Kulathinal RJ, Kumar NB, Kwon BS, Le A, Lea MA, Lee HY, Lichtor T, Lin LT, Locasale JW, Lokeshwar BL, Longo VD, Lyssiotis CA, MacKenzie KL, Malhotra M, Marino M, Martinez-Chantar ML, Matheu A, Maxwell C, McDonnell E, Meeker AK, Mehrmohamadi M, Mehta K, Michelotti GA, Mohammad RM, Mohammed SI, Morre DJ, Muralidhar V, Muqbil I, Murphy MP, Nagaraju GP, Nahta R, Niccolai E, Nowsheen S, Panis C, Pantano F, Parslow VR, Pawelec G, Pedersen PL, Poore B, Poudyal D, Prakash S, Prince M, Raffaghello L, Rathmell JC, Rathmell WK, Ray SK, Reichrath J, Rezazadeh S, Ribatti D, Ricciardiello L, Robey RB, Rodier F, Rupasinghe HP, Russo GL, Ryan EP, Samadi AK, Sanchez-Garcia I, Sanders AJ, Santini D, Sarkar M, Sasada T, Saxena NK, Shackelford RE, Shantha Kumara HM, Sharma D, Shin DM, Sidransky D, Siegelin MD, Signori E, Singh N, Sivanand S, Sliva D, Smythe C, Spagnuolo C, Stafforini DM, Stagg J, Subbarayan PR, Sundin T, Talib WH, Thompson SK, Tran PT, Ungefroren H, Vander Heiden MG, Venkateswaran V, Vinay DS, Vlachostergios PJ, Wang Z, Wellen KE, Whelan RL, Yang ES, Yang H, Yang X, Yaswen P, Yedjou C, Yin X, Zhu J, Zollo M.Semin Cancer Biol. 2015 Dec;35 Suppl:S276-304. doi: 10.1016/j.semcancer.2015.09.007. Review.PMID:26590477
- Dysregulated metabolism contributes to oncogenesis. Hirschey MD, DeBerardinis RJ, Diehl AM, Drew JE, Frezza C, Green MF, Jones LW, Ko YH, Le A, Lea MA, Locasale JW, Longo VD, Lyssiotis CA, McDonnell E, Mehrmohamadi M, Michelotti G, Muralidhar V, Murphy MP, Pedersen PL, Poore B, Raffaghello L, Rathmell JC, Sivanand S, Vander Heiden MG, Wellen KE; Target Validation Team. Semin Cancer Biol. 2015 Dec;35 Suppl:S129-50. doi: 10.1016/j.semcancer.2015.10.002. Epub 2015 Oct 8. Review.PMID:26454069