Publicação
The role of metabolism in the sensitivity of Saccharomyces cerevisiae to the anti-cancer agent cisplatin
| Resumo: | Cisplatin is a chemotherapeutic drug that can generate unrepairable DNA damage in rapidly proliferating cells, thus inducing a permanent cell cycle arrest or cell death. Currently, it is used in the treatment of patients with testicular, ovarian, head and neck, colorectal, bladder and lung cancers. There is accumulating evidence concerning cisplatin side effects, being chemoresistance the major obstacle for the use of this drug. Several studies demonstrate that cisplatin resistance is a multifactorial problem, involving defects in mismatch repair, aneuploidy, increased detoxification and failure to undergo apoptosis. Additionally, cisplatin cytotoxicity is affected by tumor cell metabolism, since research conducted in cancer cell lines revealed that a decrease in glucose uptake causes cisplatin resistance. High uptake of glucose associated to lactic acid production is a characteristic metabolic marker of cancer cells. It was first described by Otto Warburg, who noticed that cancer cells repress oxidative metabolism even in the presence of oxygen, exhibiting what is known as a glycolytic metabolism. During the last years, studies were conducted using cell cultures, to elucidate the pathways that can be responsible for cisplatin resistance. Nonetheless, studies in Saccharomyces cerevisiae have also advanced this field, since yeast and cancer cells share metabolic similarities; as Crabtree-positive yeasts, these cells also have the ability to adjust their metabolism according to environmental conditions. In the presence of glucose, the main metabolic pathway for energy is fermentation; however, when glucose is in lower concentrations or non-fermentable carbon sources are available, oxidative phosphorylation is the main energy pathway. Previous studies uncovered that when yeast cells are exposed to cisplatin in glucose-containing media cytotoxicity is higher than when a non-fermentable carbon source is available. Therefore, the aim of this project was to understand the role of metabolism in cisplatin-induced regulated cell death, using S. cerevisiae as a eukaryote model. |
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| Autores principais: | Amaral, Leslie Ann Silva |
| Assunto: | Ciências Naturais::Ciências Biológicas |
| Ano: | 2018 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade do Minho |
| Idioma: | inglês |
| Origem: | RepositóriUM - Universidade do Minho |
| Resumo: | Cisplatin is a chemotherapeutic drug that can generate unrepairable DNA damage in rapidly proliferating cells, thus inducing a permanent cell cycle arrest or cell death. Currently, it is used in the treatment of patients with testicular, ovarian, head and neck, colorectal, bladder and lung cancers. There is accumulating evidence concerning cisplatin side effects, being chemoresistance the major obstacle for the use of this drug. Several studies demonstrate that cisplatin resistance is a multifactorial problem, involving defects in mismatch repair, aneuploidy, increased detoxification and failure to undergo apoptosis. Additionally, cisplatin cytotoxicity is affected by tumor cell metabolism, since research conducted in cancer cell lines revealed that a decrease in glucose uptake causes cisplatin resistance. High uptake of glucose associated to lactic acid production is a characteristic metabolic marker of cancer cells. It was first described by Otto Warburg, who noticed that cancer cells repress oxidative metabolism even in the presence of oxygen, exhibiting what is known as a glycolytic metabolism. During the last years, studies were conducted using cell cultures, to elucidate the pathways that can be responsible for cisplatin resistance. Nonetheless, studies in Saccharomyces cerevisiae have also advanced this field, since yeast and cancer cells share metabolic similarities; as Crabtree-positive yeasts, these cells also have the ability to adjust their metabolism according to environmental conditions. In the presence of glucose, the main metabolic pathway for energy is fermentation; however, when glucose is in lower concentrations or non-fermentable carbon sources are available, oxidative phosphorylation is the main energy pathway. Previous studies uncovered that when yeast cells are exposed to cisplatin in glucose-containing media cytotoxicity is higher than when a non-fermentable carbon source is available. Therefore, the aim of this project was to understand the role of metabolism in cisplatin-induced regulated cell death, using S. cerevisiae as a eukaryote model. |
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