Publicação
Ursolic and Oleanolic acid effects on cellular cholesterol and impact on signaling pathways of cell death and proliferation
| Resumo: | Cancer is a disease characterized by the uncontrolled growth of abnormal cells that beyond the limits of a cell division in normal conditions. Colorectal cancer (CRC) is the third most common tumors and is a major cause of cancer related death worldwide. Cholesterol metabolism has been established as possible source of therapeutic targets in cancer progression, because the cholesterol synthesis pathway provides farnesyl pyrophosphates groups essential to prenylation of proteins involved in cell proliferation and cancer growth. For this reason, targeting cholesterol synthesis with statins (HMG CoA reductase inhibitors) has been explored but with limited results in the clinic due to the toxicity of high dose statin treatment. Additionally, cholesterol is involved in proliferative cell signalling through receptors activation upstream of RAS and PI3K because it is a major constituent of lipid rafts. Thus, the aim of this project is to test if natural compounds with structure similar to cholesterol, such ursolic acid (UA) and oleanolic acid (OA) can alter the lipid composition and influence signalling pathways in order to inhibit the proliferative activity of carcinoma colorectal cells (HCT116). For this we evaluated the effect of the triterpenoids in the amount of cellular cholesterol by cholesterol quantification assay and found that the UA reduces and OA increase cholesterol cellular levels. These effects may be affect AKT signaling pathway induced by insulin because our results indicate that UA, but not OA, causes a decrease in p-AKT. Furthermore, by the method of nuclear condensation we evaluated apoptosis, and both the UA and OA increased tumor necrosis factor alpha (TNF-α) induced apoptosis. These results help to take another step in understanding the mechanisms of action of these natural compounds, helping control the progression of cancer. |
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| Autores principais: | Machado, Cátia Daniela Oliveira Lima Ferreira |
| Assunto: | Ciências Naturais::Ciências Biológicas Ciências Médicas::Medicina Clínica |
| Ano: | 2015 |
| 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: | Cancer is a disease characterized by the uncontrolled growth of abnormal cells that beyond the limits of a cell division in normal conditions. Colorectal cancer (CRC) is the third most common tumors and is a major cause of cancer related death worldwide. Cholesterol metabolism has been established as possible source of therapeutic targets in cancer progression, because the cholesterol synthesis pathway provides farnesyl pyrophosphates groups essential to prenylation of proteins involved in cell proliferation and cancer growth. For this reason, targeting cholesterol synthesis with statins (HMG CoA reductase inhibitors) has been explored but with limited results in the clinic due to the toxicity of high dose statin treatment. Additionally, cholesterol is involved in proliferative cell signalling through receptors activation upstream of RAS and PI3K because it is a major constituent of lipid rafts. Thus, the aim of this project is to test if natural compounds with structure similar to cholesterol, such ursolic acid (UA) and oleanolic acid (OA) can alter the lipid composition and influence signalling pathways in order to inhibit the proliferative activity of carcinoma colorectal cells (HCT116). For this we evaluated the effect of the triterpenoids in the amount of cellular cholesterol by cholesterol quantification assay and found that the UA reduces and OA increase cholesterol cellular levels. These effects may be affect AKT signaling pathway induced by insulin because our results indicate that UA, but not OA, causes a decrease in p-AKT. Furthermore, by the method of nuclear condensation we evaluated apoptosis, and both the UA and OA increased tumor necrosis factor alpha (TNF-α) induced apoptosis. These results help to take another step in understanding the mechanisms of action of these natural compounds, helping control the progression of cancer. |
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