Publicação
The role of mitochondrial adaptations in the acquisition of the phenotype induced by LDL in breast cancer
| Resumo: | Cancer cells can acquire biological capabilities that enable tumor growth and dissemination, including the reprograming of their metabolism in order to obtain the necessary energy and metabolic intermediates to sustain tumor proliferation. The energetic reprogramming in cancer was first proposed by Otto Warburg, who suggested an anomalous energetic metabolism in cancer cells. This metabolic adaptation is characterized by an increased dependence on mitochondrial respiration and fatty acid boxidation (FAO), which has been recently correlated with increased tumor progression and aggressiveness and is recognized as a critical metabolic pathway in triple negative breast cancer (TNBC) cells, an aggressive subtype of breast cancer which has poor prognosis due to its largely resistance to conventional chemotherapy. Exposure of triple negative breast cancer cells to lipid-enriched environments, namely LDL, leads to the acquisition of an aggressive phenotype, characterized by increased proliferative and migratory capacities of the cells. Currently, the metabolic pathways responsible for the acquisition of the LDL-induced phenotype in TNBC cells remain unknown. The aim of this project is to characterize the metabolic program adopted by MDA-MB-231 TNBC cells exposed to LDL and determine its implication in the acquisition of the aggressive phenotype conferred by LDL, which is characterized by increased proliferative and migratory capacities. We investigated the expression of key regulators of mitochondrial biogenesis, glycolysis, oxidative phosphorylation (OXPHOS) and FAO to assess the deregulated metabolic pathways adopted by MDA-MB-231 cells and also investigated whether such modulations of metabolic pathways were conserved in other TNBC cell line, MDA-MB-436 and in the MCF-7 Luminal A breast cancer subtype. By inhibiting key enzymes of glycolysis, OXPHOS and FAO we have identified the metabolic pathways preferentially adopted by MDA-MB-231 cells to sustain their proliferation and migration capacities. We next investigated the impact of LDL exposure in the mitochondrial mass, mitochondrial membrane potential and mitochondrial dynamics of MDA-MB-231 cells and its implications in the aggressive phenotype induced by LDL. In conclusion, we identified metabolic adaptations of MDA-MB-231 cells exposed to LDL. We observed that MDA-MB-231 cells can reprogram their metabolism in presence of high amounts of extracellular lipids relying on glycolysis and OXPHOS to proliferate and migrate. The presence of exogenous LDL leads to adoption of a glycolytic phenotype related with PGC-1a modulation. Mitochondrial metabolism play a role in the aggressiveness of TNBC, characterized by increased mitochondria number and modulation of mitochondrial dynamics. We also identified PA as one of the components of the LDL molecule responsible for the modulation of the aggressive phenotype of TNBC. |
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| Autores principais: | Monteiro, Susana Cristina Cachapa |
| Assunto: | Cancer metabolism Mitochondria Triple negative breast cancer Fatty acid oxidation Oxidative phosphorylation Teses de mestrado - 2017 |
| Ano: | 2017 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Cancer cells can acquire biological capabilities that enable tumor growth and dissemination, including the reprograming of their metabolism in order to obtain the necessary energy and metabolic intermediates to sustain tumor proliferation. The energetic reprogramming in cancer was first proposed by Otto Warburg, who suggested an anomalous energetic metabolism in cancer cells. This metabolic adaptation is characterized by an increased dependence on mitochondrial respiration and fatty acid boxidation (FAO), which has been recently correlated with increased tumor progression and aggressiveness and is recognized as a critical metabolic pathway in triple negative breast cancer (TNBC) cells, an aggressive subtype of breast cancer which has poor prognosis due to its largely resistance to conventional chemotherapy. Exposure of triple negative breast cancer cells to lipid-enriched environments, namely LDL, leads to the acquisition of an aggressive phenotype, characterized by increased proliferative and migratory capacities of the cells. Currently, the metabolic pathways responsible for the acquisition of the LDL-induced phenotype in TNBC cells remain unknown. The aim of this project is to characterize the metabolic program adopted by MDA-MB-231 TNBC cells exposed to LDL and determine its implication in the acquisition of the aggressive phenotype conferred by LDL, which is characterized by increased proliferative and migratory capacities. We investigated the expression of key regulators of mitochondrial biogenesis, glycolysis, oxidative phosphorylation (OXPHOS) and FAO to assess the deregulated metabolic pathways adopted by MDA-MB-231 cells and also investigated whether such modulations of metabolic pathways were conserved in other TNBC cell line, MDA-MB-436 and in the MCF-7 Luminal A breast cancer subtype. By inhibiting key enzymes of glycolysis, OXPHOS and FAO we have identified the metabolic pathways preferentially adopted by MDA-MB-231 cells to sustain their proliferation and migration capacities. We next investigated the impact of LDL exposure in the mitochondrial mass, mitochondrial membrane potential and mitochondrial dynamics of MDA-MB-231 cells and its implications in the aggressive phenotype induced by LDL. In conclusion, we identified metabolic adaptations of MDA-MB-231 cells exposed to LDL. We observed that MDA-MB-231 cells can reprogram their metabolism in presence of high amounts of extracellular lipids relying on glycolysis and OXPHOS to proliferate and migrate. The presence of exogenous LDL leads to adoption of a glycolytic phenotype related with PGC-1a modulation. Mitochondrial metabolism play a role in the aggressiveness of TNBC, characterized by increased mitochondria number and modulation of mitochondrial dynamics. We also identified PA as one of the components of the LDL molecule responsible for the modulation of the aggressive phenotype of TNBC. |
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