TP53 mutation hits energy metabolism and increases glycolysis in breast cancer
| Autor: | Laszlo Tretter, András Szabó, Balázs Győrffy, Attila Ambrus, Lőrinc S. Pongor, Hajnalka Harami-Papp, Peter Hauser, Ádám Nagy, Gyöngyi Munkácsy, Gergő Horváth |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Tumor suppressor gene Mutant Breast Neoplasms Biology medicine.disease_cause 03 medical and health sciences 0302 clinical medicine Breast cancer breast cancer Cell Line Tumor medicine Humans glycolytic efficiency Genetics next generation sequencing Mutation FBP1 Wild type Cancer medicine.disease Warburg effect 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer research Female Tumor Suppressor Protein p53 Energy Metabolism Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Hajnalka Harami-Papp 1, * , Lőrinc S. Pongor 1, 3, * , Gyongyi Munkacsy 1 , Gergő Horvath 2 , Adam M. Nagy 2 , Attila Ambrus 2 , Peter Hauser 3 , Andras Szabo 3 , Laszlo Tretter 2 , Balazs Győrffy 1 1 MTA TTK Lendulet Cancer Biomarker Research Group, H-1117, Budapest, Hungary 2 Semmelweis University, Department of Medical Biochemistry, H-1094, Budapest, Hungary 3 Semmelweis University, Second Department of Pediatrics, H-1094, Budapest, Hungary * These authors have contributed equally to this work Correspondence to: Balazs Győrffy, email: gyorffy.balazs@ttk.mta.hu Laszlo Tretter, email: tretter.laszlo@med.semmelweis-univ.hu Keywords: glycolytic efficiency, breast cancer, Warburg effect, next generation sequencing Received: May 24, 2016 Accepted: August 13, 2016 Published: August 25, 2016 ABSTRACT Promising new hallmarks of cancer is alteration of energy metabolism that involves molecular mechanisms shifting cancer cells to aerobe glycolysis. Our goal was to evaluate the correlation between mutation in the commonly mutated tumor suppressor gene TP53 and metabolism. We established a database comprising mutation and RNA-seq expression data of the TCGA repository and performed receiver operating characteristics (ROC) analysis to compare expression of each gene between TP53 mutated and wild type samples. All together 762 breast cancer samples were evaluated of which 215 had TP53 mutation. Top up-regulated metabolic genes include glycolytic enzymes ( e.g. HK3, GPI, GAPDH, PGK1 , ENO1 ), glycolysis regulator ( PDK1 ) and pentose phosphate pathway enzymes ( PGD, TKT , RPIA ). Gluconeogenesis enzymes ( G6PC3, FBP1 ) were down-regulated. Oxygen consumption and extracellular acidification rates were measured in TP53 wild type and mutant breast cell lines with a microfluorimetric analyzer. Applying metabolic inhibitors in the presence and absence of D-glucose and L-glutamine in cell culture experiments resulted in higher glycolytic and mitochondrial activity in TP53 mutant breast cancer cell lines. In summary, TP53 mutation influences energy metabolism at multiple levels. Our results provide evidence for the synergistic activation of multiple hallmarks linking to these the mutation status of a key driver gene. |
| Databáze: | OpenAIRE |
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