Amoedo 2015 Abstract MiP2015
|The energy requirement of metastatic cells.|
Rodrigues MF, Obre E, Melo F, Gilson Jr, Galina A, Jasiulionis M, Rossignol R, Rumjanek FD, Amoedo ND (2015)
Many tumor cells show enhanced aerobic glycolysis, even in the presence of oxygen: The so called Warburg effect. This pathway provides substrates for the synthesis of lipids, proteins and DNA. However, the Warburg effect does not necessarily imply mitochondrial dysfunction. Research currently pictures tumors as compositions of different populations of cells with distinct metabolic phenotypes, which are able to adjust to oxygen and nutrient gradients within the tumor mass. Not all cancer cells display a high glycolytic flux as proposed by Warburg. Our results indicate that progression to metastasis requires mitochondrial function. Our research, centered on cell lines that display increasing degrees of malignancy, focuses on metabolic events, especially those involving mitochondria, which could reveal which stages are mechanistically associated to metastasis. The experimental model consisted of murine melanocytes. These cells were subjected to several cycles of adhesion impediment, producing stable cell lines exhibiting phenotypes representing a progression from non-tumorigenic to metastatic cells. These were: non-tumorigenic cells melana (ma), non-tumorigenic cell line 4C (obtained after four cycles of adherence abrogation), non-metastatic 4C11- and metastatic 4C11+ melanoma cell lines . The metabolic profile of each of these different cell lines was investigated by evaluating enzymatic activities and expression of members of the glycolytic and oxidative pathways. Our results show that only metastatic cell line (4C11+) released the highest amounts of lactate may derived from glutamine catabolism. Results from measurements with high-resolution respirometry (HRR) show that 4C11+ intact cells increased (2.8x) oxidative metabolism, with enhanced (2.6x) rates of oxygen consumption coupled to ATP synthesis, when compared to the other pre-malignant stages. We did not observe an increase in mitochondrial content, mitochondrial biogenesis and alterations of mitochondrial morphology. In addition, in 4C11+ cells, we observed an increase in ATP content, succinate oxidation (Complex II activity) and fatty-acid oxidation. In addition, 4C11+ cells exhibited a two fold increase in mitochondrial membrane potential (ΔΨmit). Metabolomic analysis revealed that 4C11+ cells could be grouped as a subpopulation whose profile was quite distinct from the other cells investigated here. Furthermore we were able to show that the migration of cells depended on glutaminase activity. The results presented here have centered on how the multiple metabolic inputs of tumor cells may converge to compose the so called metastatic phenotype.
• Keywords: Mitochondria, Metabolic profile, Metastatic phenotype
• O2k-Network Lab: BR Rio de Janeiro Rumjanek FD, BR Rio de Janeiro Galina A, BR Rio de Janeiro Institute Biomedical Chemistry, FR Bordeaux Rossignol R
Labels: MiParea: Respiration, mt-Biogenesis;mt-density, mt-Membrane Pathology: Cancer
Organism: Mouse, Rat Tissue;cell: Other cell lines
Pathway: F, S HRR: Oxygraph-2k Event: A2, Oral MiP2015
1-Inst Bioquímica Médica Leopoldo De Meis, UFRJ, Rio de Janeiro, Brazil; 2- Dept Farmacologia, Univ Federal de São Paulo, Brazil; 3-Maladies Rares: Génétique ET Métabolisme, Univ Bordeaux Segalen, France. - [email protected]
- Oba-Shinjo SM, Correa M, Ricca TI, Molognoni F, Pinhal MA, Neves IA, Marie SK, Sampaio LO, Nader HB, Chammas R, Jasiulionis MG (2006) Melanocyte transformation associated with substrate adhesion impediment. Neoplasia 8:231-41.