Prostate Cancer Metabolism in the Interplay of Obesity and Estrogens Actions
Autor(a) principal: | |
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Data de Publicação: | 2018 |
Tipo de documento: | Dissertação |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10400.6/9811 |
Resumo: | Cancers have a common ability of reprogramming energy metabolism, which is known as a hallmark of cancer. In order to satisfy their needs, cancer cells reorganized metabolic activity upregulating glycolysis rate, which allows cells to maintain high biosynthesis levels of lipids and other macromolecules, sustaining high proliferation rates. The high energy demands of cancer cells are fulfilled by anaerobic glycolysis, even in the presence of oxygen, which results in high rates of lactate production. The excess of lactate exported to the extracellular medium increases acidity and suppresses host anticancer immunity, which favours cancer cells growth and invasion. Besides glucose, fatty acids are another important energetic source, and its oxidation and biosynthesis seems to be augmented in cancer cells. Androgens are well-known drivers in development and progression of PCa. In addition, in hormone-dependent cancers, such as breast and prostate cancer, steroid hormones have been identified as important modulators of metabolic pathways. Our research group and others have demonstrated the role of androgens as stimulators of PCa by modulating glucose consumption and lactate production, as well as the distinct metabolic profile between non-neoplastic cell line, PNT1A, and neoplastic cell lines, LNCaP and PC3. However, in the last years, estrogens had also been implicated in the carcinogenesis of the prostate, despite some studies defend their protective effect. Obesity is a worldwide epidemic characterized by a disruption in adipose tissue that is associated with a stage of hyperestrogenism. In addition, obesity has been identified as a factor for aggressiveness and poor prognosis of PCa. The present work aims to evaluate the role of 17ß-Estradiol (E2) on modulating the glycolytic metabolism and lipid metabolism in human prostate cell lines, and to understand its action as stimulator of the development and progression of PCa. Non-neoplastic (PNT1A) and neoplastic (LNCaP and PC3) human prostate cell lines were cultured in presence or absence of 0,1; 1 e 100 nM de E2 for 24, 48 e 72 h. The 1 nM concentration and a treatment period of 48 h were the conditions selected to evaluate the effect of E2 on glycolytic and lipid metabolism in all cell lines under study. Protein expression and activity of target modulators of these biological processes were assessed by means of Western blot analysis and biochemical assays. The obtained results showed that treatment with E2 augmented glucose consumption and lactate production in PNT1A, LNCaP and PC3 cell lines. These results were underpinned by the increased expression or activity of glucose transporters and glycolytic enzymes. Besides that, E2-treatment increased the expression of lipid regulators in all cell lines, which demonstrate its action regulating lipid metabolism. To conclude, the obtained results showed that E2 might have a role in the development and progression of PCa by stimulating the glycolytic and lipid metabolism in both non-neoplastic and neoplastic cells. Moreover, the evidence gathered hereom follow the studies that defend the causative role of E2 in PCa. Finally, a relationship between estrogens, obesity and PCa might be likely established since hyperestrogenism may increase the odds for tumour development and invasion by potentiating the metabolic reprogramming of cancer cells. |
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Prostate Cancer Metabolism in the Interplay of Obesity and Estrogens ActionsCancro da PróstataEstrogéniosLncapMetabolismo GlicolíticoMetabolismo LipídicoPc3Pnt1aDomínio/Área Científica::Ciências Médicas::Ciências BiomédicasCancers have a common ability of reprogramming energy metabolism, which is known as a hallmark of cancer. In order to satisfy their needs, cancer cells reorganized metabolic activity upregulating glycolysis rate, which allows cells to maintain high biosynthesis levels of lipids and other macromolecules, sustaining high proliferation rates. The high energy demands of cancer cells are fulfilled by anaerobic glycolysis, even in the presence of oxygen, which results in high rates of lactate production. The excess of lactate exported to the extracellular medium increases acidity and suppresses host anticancer immunity, which favours cancer cells growth and invasion. Besides glucose, fatty acids are another important energetic source, and its oxidation and biosynthesis seems to be augmented in cancer cells. Androgens are well-known drivers in development and progression of PCa. In addition, in hormone-dependent cancers, such as breast and prostate cancer, steroid hormones have been identified as important modulators of metabolic pathways. Our research group and others have demonstrated the role of androgens as stimulators of PCa by modulating glucose consumption and lactate production, as well as the distinct metabolic profile between non-neoplastic cell line, PNT1A, and neoplastic cell lines, LNCaP and PC3. However, in the last years, estrogens had also been implicated in the carcinogenesis of the prostate, despite some studies defend their protective effect. Obesity is a worldwide epidemic characterized by a disruption in adipose tissue that is associated with a stage of hyperestrogenism. In addition, obesity has been identified as a factor for aggressiveness and poor prognosis of PCa. The present work aims to evaluate the role of 17ß-Estradiol (E2) on modulating the glycolytic metabolism and lipid metabolism in human prostate cell lines, and to understand its action as stimulator of the development and progression of PCa. Non-neoplastic (PNT1A) and neoplastic (LNCaP and PC3) human prostate cell lines were cultured in presence or absence of 0,1; 1 e 100 nM de E2 for 24, 48 e 72 h. The 1 nM concentration and a treatment period of 48 h were the conditions selected to evaluate the effect of E2 on glycolytic and lipid metabolism in all cell lines under study. Protein expression and activity of target modulators of these biological processes were assessed by means of Western blot analysis and biochemical assays. The obtained results showed that treatment with E2 augmented glucose consumption and lactate production in PNT1A, LNCaP and PC3 cell lines. These results were underpinned by the increased expression or activity of glucose transporters and glycolytic enzymes. Besides that, E2-treatment increased the expression of lipid regulators in all cell lines, which demonstrate its action regulating lipid metabolism. To conclude, the obtained results showed that E2 might have a role in the development and progression of PCa by stimulating the glycolytic and lipid metabolism in both non-neoplastic and neoplastic cells. Moreover, the evidence gathered hereom follow the studies that defend the causative role of E2 in PCa. Finally, a relationship between estrogens, obesity and PCa might be likely established since hyperestrogenism may increase the odds for tumour development and invasion by potentiating the metabolic reprogramming of cancer cells.A capacidade das células tumorais reprogramarem o seu metabolismo emergiu, nos últimos anos, como um dos principais “hallmark” do cancro. De forma a satisfazer as suas necessidades energéticas, as células cancerígenas reorganizam a sua atividade metabólica, aumentam a taxa de glicólise e, dessa forma, conseguem manter os altos níveis de biossíntese de lípidos e outras macromoléculas, assim como as altas taxas de proliferação. Esta grande exigência energética das células cancerígenas é traduzida pela ativação da glicólise anaeróbica, mesmo na presença de oxigénio, o que resulta numa elevada produção de lactato. O excesso deste metabolito aumenta a acidez extracelular, suprime a autoimunidade do hospedeiro e favorece a invasão e divisão das células cancerígenas. Para além da glicose, os ácidos gordos são outra fonte energética das células e a sua via oxidativa e de síntese parecem estar aumentadas nas células cancerígenas. O papel dos androgénios como promotores do desenvolvimento e progressão do cancro da próstata é bem conhecido. Para além disso, em cancros hormono-dependentes, como cancro da mama e da próstata, as hormonas esteroides foram identificadas como importantes moduladores de vias metabólicas das células cancerígenas. Estudos anteriores do nosso e de outros grupos de investigação demonstraram o papel dos androgénios como estimuladores do cancro da próstata ao regularem o consumo da glucose e a produção de lactato, e caracterizam o perfil metabólico de linhas celulares de próstata não-neoplásica, PNT1A, e de linhas neoplásicas, LNCaP e PC3. No entanto, nos últimos anos, os estrogénios também tem sido implicados na carcinogénese da próstata. A obesidade é uma epidemia a nível global caracterizada por uma quebra no normal funcionamento do tecido adiposo sendo associada a um estado de hiperestrogenismo. Para além disso, a obesidade tem sido identificada como um fator para um aumento da agressividade tumoral e de mau prognóstico no cancro da próstata. O presente trabalho teve como objetivo avaliar o papel do 17ß-Estradiol (E2) na modulação do metabolismo glicolítico e lipídico das linhas celulares de próstata humana de forma a perceber a sua ação como estimulador do desenvolvimento e progressão do cancro. Para isso, linhas celulares de próstata humana não neoplásicas (PNT1A) e neoplásicas (LNCaP) foram mantidas em cultura na presença ou ausência de 0,1; 1 e 100 nM de E2 durante 24, 48 e 72 horas. A concentração de 1 nM e o tempo de tratamento de 48 horas foram as condições selecionadas para avaliação dos efeitos do E2 no metabolismo glicolítico e lipídico nos diferentes modelos celulares em estudo (PNT1A, LNCaP e PC3). A expressão proteica e a atividade dos moduladores alvo destes processos foram analisados por Western Blot e ensaios bioquímicos. Os resultados obtidos revelam que o tratamento com E2 estimulou o fluxo glicolítico ao aumentar o consumo de glucose e a produção de lactato nas células PNT1A, LNCaP e PC3. Estes resultados foram suportados pelo aumento da expressão ou atividade dos transportadores de glicose e enzimas glicolíticas. Para além disso, o tratamento com E2 também aumentou a expressão de proteínas envolvidas na incorporação de lípidos e na sua ß-oxidação, assim como na síntese. Efeitos estes que foram observados em todas as linhas celulares (neoplásicas e não-neoplásicas), o que é demonstrativo da forte ação do E2 na regulação do metabolismo lipídico. Para concluir, os resultados obtidos sugerem que o E2 pode ter um papel no desenvolvimento e progressão do cancro da próstata ao estimular a via glicolítica e lipídica quer nas células não-neoplásicas quer neoplásicas. Além disso, as evidências deste trabalho suportam os estudos que defendem o papel causador do E2 no cancro da próstata. Mais ainda, a relação entre estrogénios, obesidade e o cancro da próstata pode ser estabelecida uma vez que o hiperestrogenismo pode aumentar a probabilidade de desenvolvimento e invasão tumoral ao potenciar a reprogramação metabólica das células cancerígenas.Socorro, Sílvia Cristina da Cruz MarquesVaz, CátiauBibliorumMonteiro, Joana Filipe Gomes Araújo Macário2020-03-06T16:56:54Z2018-10-262018-10-42018-10-26T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/10400.6/9811TID:202354148enginfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-12-15T09:51:07Zoai:ubibliorum.ubi.pt:10400.6/9811Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T00:49:53.218216Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Prostate Cancer Metabolism in the Interplay of Obesity and Estrogens Actions |
title |
Prostate Cancer Metabolism in the Interplay of Obesity and Estrogens Actions |
spellingShingle |
Prostate Cancer Metabolism in the Interplay of Obesity and Estrogens Actions Monteiro, Joana Filipe Gomes Araújo Macário Cancro da Próstata Estrogénios Lncap Metabolismo Glicolítico Metabolismo Lipídico Pc3 Pnt1a Domínio/Área Científica::Ciências Médicas::Ciências Biomédicas |
title_short |
Prostate Cancer Metabolism in the Interplay of Obesity and Estrogens Actions |
title_full |
Prostate Cancer Metabolism in the Interplay of Obesity and Estrogens Actions |
title_fullStr |
Prostate Cancer Metabolism in the Interplay of Obesity and Estrogens Actions |
title_full_unstemmed |
Prostate Cancer Metabolism in the Interplay of Obesity and Estrogens Actions |
title_sort |
Prostate Cancer Metabolism in the Interplay of Obesity and Estrogens Actions |
author |
Monteiro, Joana Filipe Gomes Araújo Macário |
author_facet |
Monteiro, Joana Filipe Gomes Araújo Macário |
author_role |
author |
dc.contributor.none.fl_str_mv |
Socorro, Sílvia Cristina da Cruz Marques Vaz, Cátia uBibliorum |
dc.contributor.author.fl_str_mv |
Monteiro, Joana Filipe Gomes Araújo Macário |
dc.subject.por.fl_str_mv |
Cancro da Próstata Estrogénios Lncap Metabolismo Glicolítico Metabolismo Lipídico Pc3 Pnt1a Domínio/Área Científica::Ciências Médicas::Ciências Biomédicas |
topic |
Cancro da Próstata Estrogénios Lncap Metabolismo Glicolítico Metabolismo Lipídico Pc3 Pnt1a Domínio/Área Científica::Ciências Médicas::Ciências Biomédicas |
description |
Cancers have a common ability of reprogramming energy metabolism, which is known as a hallmark of cancer. In order to satisfy their needs, cancer cells reorganized metabolic activity upregulating glycolysis rate, which allows cells to maintain high biosynthesis levels of lipids and other macromolecules, sustaining high proliferation rates. The high energy demands of cancer cells are fulfilled by anaerobic glycolysis, even in the presence of oxygen, which results in high rates of lactate production. The excess of lactate exported to the extracellular medium increases acidity and suppresses host anticancer immunity, which favours cancer cells growth and invasion. Besides glucose, fatty acids are another important energetic source, and its oxidation and biosynthesis seems to be augmented in cancer cells. Androgens are well-known drivers in development and progression of PCa. In addition, in hormone-dependent cancers, such as breast and prostate cancer, steroid hormones have been identified as important modulators of metabolic pathways. Our research group and others have demonstrated the role of androgens as stimulators of PCa by modulating glucose consumption and lactate production, as well as the distinct metabolic profile between non-neoplastic cell line, PNT1A, and neoplastic cell lines, LNCaP and PC3. However, in the last years, estrogens had also been implicated in the carcinogenesis of the prostate, despite some studies defend their protective effect. Obesity is a worldwide epidemic characterized by a disruption in adipose tissue that is associated with a stage of hyperestrogenism. In addition, obesity has been identified as a factor for aggressiveness and poor prognosis of PCa. The present work aims to evaluate the role of 17ß-Estradiol (E2) on modulating the glycolytic metabolism and lipid metabolism in human prostate cell lines, and to understand its action as stimulator of the development and progression of PCa. Non-neoplastic (PNT1A) and neoplastic (LNCaP and PC3) human prostate cell lines were cultured in presence or absence of 0,1; 1 e 100 nM de E2 for 24, 48 e 72 h. The 1 nM concentration and a treatment period of 48 h were the conditions selected to evaluate the effect of E2 on glycolytic and lipid metabolism in all cell lines under study. Protein expression and activity of target modulators of these biological processes were assessed by means of Western blot analysis and biochemical assays. The obtained results showed that treatment with E2 augmented glucose consumption and lactate production in PNT1A, LNCaP and PC3 cell lines. These results were underpinned by the increased expression or activity of glucose transporters and glycolytic enzymes. Besides that, E2-treatment increased the expression of lipid regulators in all cell lines, which demonstrate its action regulating lipid metabolism. To conclude, the obtained results showed that E2 might have a role in the development and progression of PCa by stimulating the glycolytic and lipid metabolism in both non-neoplastic and neoplastic cells. Moreover, the evidence gathered hereom follow the studies that defend the causative role of E2 in PCa. Finally, a relationship between estrogens, obesity and PCa might be likely established since hyperestrogenism may increase the odds for tumour development and invasion by potentiating the metabolic reprogramming of cancer cells. |
publishDate |
2018 |
dc.date.none.fl_str_mv |
2018-10-26 2018-10-4 2018-10-26T00:00:00Z 2020-03-06T16:56:54Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/masterThesis |
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masterThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10400.6/9811 TID:202354148 |
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http://hdl.handle.net/10400.6/9811 |
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TID:202354148 |
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eng |
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eng |
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