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‣ Metabolism and brain cancer

MARIE, Suely Kazue Nagahashi; SHINJO, Sueli Mieko Oba
Fonte: Faculdade de Medicina / USP Publicador: Faculdade de Medicina / USP
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
46.965522%
Cellular energy metabolism is one of the main processes affected during the transition from normal to cancer cells, and it is a crucial determinant of cell proliferation or cell death. As a support for rapid proliferation, cancer cells choose to use glycolysis even in the presence of oxygen (Warburg effect) to fuel macromolecules for the synthesis of nucleotides, fatty acids, and amino acids for the accelerated mitosis, rather than fuel the tricarboxylic acid cycle and oxidative phosphorylation. Mitochondria biogenesis is also reprogrammed in cancer cells, and the destiny of those cells is determined by the balance between energy and macromolecule supplies, and the efficiency of buffering of the cumulative radical oxygen species. In glioblastoma, the most frequent and malignant adult brain tumor, a metabolic shift toward aerobic glycolysis is observed, with regulation by well known genes as integrants of oncogenic pathways such as phosphoinositide 3-kinase/protein kinase, MYC, and hypoxia regulated gene as hypoxia induced factor 1. The expression profile of a set of genes coding for glycolysis and the tricarboxylic acid cycle in glioblastoma cases confirms this metabolic switch. An understanding of how the main metabolic pathways are modified by cancer cells and the interactions between oncogenes and tumor suppressor genes with these pathways may enlighten new strategies in cancer therapy. In the present review...

‣ Lactate transporters in the context of prostate cancer metabolism : what do we know?

Gomes, Nelma; Baltazar, Fátima
Fonte: Molecular Diversity Preservation International Publicador: Molecular Diversity Preservation International
Tipo: Artigo de Revista Científica
Publicado em //2014 Português
Relevância na Pesquisa
66.947227%
Lactate Transporters in the Context of Prostate Cancer Metabolism: What Do We Know?; Metabolic changes during malignant transformation have been noted for many years in tumours. Otto Warburg first reported that cancer cells preferentially rely on glycolysis for energy production, even in the presence of oxygen, leading to the production of high levels of lactate. The crucial role of lactate efflux and exchange within the tumour microenvironment drew attention to monocarboxylate transporters (MCTs). MCTs have been recognized as promising targets in cancer therapy, and their expression was described in a large variety of tumours; however, studies showing how these isoforms contribute to the acquisition of the malignant phenotype are scarce and still unclear regarding prostate cancer. In this review, we focus on the role for MCTs in cell metabolism, supporting the development and progression of prostate cancer, and discuss the exploitation of the metabolic nature of prostate cancer for therapeutic and diagnostic purposes.

‣ Metabolic signature of lung cancer: a metabolomic study of human tissues and biofluids; Assinatura metabólica do cancro do pulmão: estudo metabolómico de tecidos e biofluidos humanos

Rocha, Cláudia Manuela Mesquita da
Fonte: Universidade de Aveiro Publicador: Universidade de Aveiro
Tipo: Tese de Doutorado
Português
Relevância na Pesquisa
56.89936%
This thesis reports the application of metabolomics to human tissues and biofluids (blood plasma and urine) to unveil the metabolic signature of primary lung cancer. In Chapter 1, a brief introduction on lung cancer epidemiology and pathogenesis, together with a review of the main metabolic dysregulations known to be associated with cancer, is presented. The metabolomics approach is also described, addressing the analytical and statistical methods employed, as well as the current state of the art on its application to clinical lung cancer studies. Chapter 2 provides the experimental details of this work, in regard to the subjects enrolled, sample collection and analysis, and data processing. In Chapter 3, the metabolic characterization of intact lung tissues (from 56 patients) by proton High Resolution Magic Angle Spinning (HRMAS) Nuclear Magnetic Resonance (NMR) spectroscopy is described. After careful assessment of acquisition conditions and thorough spectral assignment (over 50 metabolites identified), the metabolic profiles of tumour and adjacent control tissues were compared through multivariate analysis. The two tissue classes could be discriminated with 97% accuracy, with 13 metabolites significantly accounting for this discrimination: glucose and acetate (depleted in tumours)...

‣ Metabolism and brain cancer

Marie,Suely Kazue Nagahashi; Shinjo,Sueli Mieko Oba
Fonte: Faculdade de Medicina / USP Publicador: Faculdade de Medicina / USP
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/01/2011 Português
Relevância na Pesquisa
46.965522%
Cellular energy metabolism is one of the main processes affected during the transition from normal to cancer cells, and it is a crucial determinant of cell proliferation or cell death. As a support for rapid proliferation, cancer cells choose to use glycolysis even in the presence of oxygen (Warburg effect) to fuel macromolecules for the synthesis of nucleotides, fatty acids, and amino acids for the accelerated mitosis, rather than fuel the tricarboxylic acid cycle and oxidative phosphorylation. Mitochondria biogenesis is also reprogrammed in cancer cells, and the destiny of those cells is determined by the balance between energy and macromolecule supplies, and the efficiency of buffering of the cumulative radical oxygen species. In glioblastoma, the most frequent and malignant adult brain tumor, a metabolic shift toward aerobic glycolysis is observed, with regulation by well known genes as integrants of oncogenic pathways such as phosphoinositide 3-kinase/protein kinase, MYC, and hypoxia regulated gene as hypoxia induced factor 1. The expression profile of a set of genes coding for glycolysis and the tricarboxylic acid cycle in glioblastoma cases confirms this metabolic switch. An understanding of how the main metabolic pathways are modified by cancer cells and the interactions between oncogenes and tumor suppressor genes with these pathways may enlighten new strategies in cancer therapy. In the present review...

‣ Accelerated aging in the tumor microenvironment: Connecting aging, inflammation and cancer metabolism with personalized medicine

Lisanti, Michael P; Martinez-Outschoorn, Ubaldo E; Pavlides, Stephanos; Whitaker-Menezes, Diana; Pestell, Richard G; Howell, Anthony; Sotgia, Federica
Fonte: Landes Bioscience Publicador: Landes Bioscience
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
46.97259%
Cancer is thought to be a disease associated with aging. Interestingly, normal aging is driven by the production of ROS and mitochondrial oxidative stress, resulting in the cumulative accumulation of DNA damage. Here, we discuss how ROS signaling, NFκB- and HIF1-activation in the tumor micro-environment induces a form of “accelerated aging,” which leads to stromal inflammation and changes in cancer cell metabolism. Thus, we present a unified model where aging (ROS), inflammation (NFκB) and cancer metabolism (HIF1), act as co-conspirators to drive autophagy (“self-eating”) in the tumor stroma. Then, autophagy in the tumor stroma provides high-energy “fuel” and the necessary chemical building blocks, for accelerated tumor growth and metastasis. Stromal ROS production acts as a “mutagenic motor” and allows cancer cells to buffer—at a distance—exactly how much of a mutagenic stimulus they receive, further driving tumor cell selection and evolution. Surviving cancer cells would be selected for the ability to induce ROS more effectively in stromal fibroblasts, so they could extract more nutrients from the stroma via autophagy. If lethal cancer is a disease of “accelerated host aging” in the tumor stroma, then cancer patients may benefit from therapy with powerful antioxidants. Antioxidant therapy should block the resulting DNA damage...

‣ Targeting Cancer Metabolism

Teicher, Beverly A.; Linehan, W. Marston; Helman, Lee J.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 15/10/2012 Português
Relevância na Pesquisa
47.039746%
The understanding that oncogenes can have profound effects on cellular metabolism and the discovery of mutations and alterations in several metabolism-related enzymes (IDH1, IDH2, SDH, FH, PKM2) has renewed interest in cancer metabolism and renewed hope of taking therapeutic advantage of cancer metabolism. Otto Warburg observed that aerobic glycolysis was a characteristic of cancer cells. More than 50-years later, we understand that aerobic glycolysis and uptake of glutamine and glycine allow cancer cells to produce energy (ATP) and the nucleotides, amino acids and lipids required for proliferation. Expression of the MYC oncogene drives the increase in cellular biomass facilitating proliferation. PKM2 expression in cancer cells stimulates aerobic glycolysis. Amongst intermediary metabolism enzyme, mutations in succinate dehydrogenase (SDH) occur in gastointestinal stromal tumors and result in a pseudohypoxic metabolic milieu. Fumarate hydratase (FH) mutations lead to a characteristic renal cell carcinoma. Isocitrate dehydrogenase (IDH1/2) mutations have been found in leukemias, gliomas, prostate cancer, colon cancer, thyroid cancer and sarcomas. These recently recognized oncogenic metabolic lesions may be selective targets for new anticancer therapeutics.

‣ The evolution of genome-scale models of cancer metabolism

Lewis, Nathan E.; Abdel-Haleem, Alyaa M.
Fonte: Frontiers Media S.A. Publicador: Frontiers Media S.A.
Tipo: Artigo de Revista Científica
Publicado em 03/09/2013 Português
Relevância na Pesquisa
47.027617%
The importance of metabolism in cancer is becoming increasingly apparent with the identification of metabolic enzyme mutations and the growing awareness of the influence of metabolism on signaling, epigenetic markers, and transcription. However, the complexity of these processes has challenged our ability to make sense of the metabolic changes in cancer. Fortunately, constraint-based modeling, a systems biology approach, now enables one to study the entirety of cancer metabolism and simulate basic phenotypes. With the newness of this field, there has been a rapid evolution of both the scope of these models and their applications. Here we review the various constraint-based models built for cancer metabolism and how their predictions are shedding new light on basic cancer phenotypes, elucidating pathway differences between tumors, and dicovering putative anti-cancer targets. As the field continues to evolve, the scope of these genome-scale cancer models must expand beyond central metabolism to address questions related to the diverse processes contributing to tumor development and metastasis.

‣ Cancer Metabolism: New Validated Targets for Drug Discovery

Sotgia, Federica; Martinez-Outschoorn, Ubaldo E.; Lisanti, Michael P.
Fonte: Impact Journals LLC Publicador: Impact Journals LLC
Tipo: Artigo de Revista Científica
Publicado em 22/07/2013 Português
Relevância na Pesquisa
46.95719%
Recent studies in cancer metabolism directly implicate catabolic fibroblasts as a new rich source of i) energy and ii) biomass, for the growth and survival of anabolic cancer cells. Conversely, anabolic cancer cells upregulate oxidative mitochondrial metabolism, to take advantage of the abundant fibroblast fuel supply. This simple model of “metabolic-symbiosis” has now been independently validated in several different types of human cancers, including breast, ovarian, and prostate tumors. Biomarkers of metabolic-symbiosis are excellent predictors of tumor recurrence, metastasis, and drug resistance, as well as poor patient survival. New pre-clinical models of metabolic-symbiosis have been generated and they genetically validate that catabolic fibroblasts promote tumor growth and metastasis. Over 30 different stable lines of catabolic fibroblasts and >10 different lines of anabolic cancer cells have been created and are well-characterized. For example, catabolic fibroblasts harboring ATG16L1 increase tumor cell metastasis by >11.5-fold, despite the fact that genetically identical cancer cells were used. Taken together, these studies provide >40 novel validated targets, for new drug discovery and anti-cancer therapy. Since anabolic cancer cells amplify their capacity for oxidative mitochondrial metabolism...

‣ Cancer metabolic reprogramming: importance, main features, and potentials for precise targeted anti-cancer therapies

Phan, Liem Minh; Yeung, Sai-Ching Jim; Lee, Mong-Hong
Fonte: Chinese Anti-Cancer Association Publicador: Chinese Anti-Cancer Association
Tipo: Artigo de Revista Científica
Publicado em /03/2014 Português
Relevância na Pesquisa
47.000947%
Cancer cells are well documented to rewire their metabolism and energy production networks to support and enable rapid proliferation, continuous growth, survival in harsh conditions, invasion, metastasis, and resistance to cancer treatments. Since Dr. Otto Warburg’s discovery about altered cancer cell metabolism in 1930, thousands of studies have shed light on various aspects of cancer metabolism with a common goal to find new ways for effectively eliminating tumor cells by targeting their energy metabolism. This review highlights the importance of the main features of cancer metabolism, summarizes recent remarkable advances in this field, and points out the potentials to translate these scientific findings into life-saving diagnosis and therapies to help cancer patients.

‣ Imaging of Gastric Cancer Metabolism Using 18 F-FDG PET/CT

Yun, Mijin
Fonte: The Korean Gastric Cancer Association Publicador: The Korean Gastric Cancer Association
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
56.711836%
Aerobic glycolysis has been the most important hypothesis in cancer metabolism. It seems to be related to increased bioenergetic and biosynthetic needs in rapidly proliferating cancer cells. To this end, F-18 fluorodeoxyglucose (FDG), a glucose analog, became widely popular for the detection of malignancies combined with positron emission tomography/computed tomography (PET/CT). Although the potential roles of FDG PET/CT in primary tumor detection are not fully established, it seems to have a limited sensitivity in detecting early gastric cancer and mainly signet ring or non-solid types of advanced gastric cancer. In evaluating lymph node metastases, the location of lymph nodes and the degree of FDG uptake in primary tumors appear to be important factors affecting the diagnostic accuracy of PET/CT. In spite of the limited sensitivity, the high specificity of PET/CT for lymph node metastases may play an important role in changing the extent of lymphadenectomy or reducing futile laparotomies. For peritoneal metastases, PET/CT seems to have a poorer sensitivity but a better specificity than CT. The roles of PET/CT in the evaluation of other distant metastases are yet to be known. Studies including primary tumors with low FDG uptake or peritoneal recurrence seem suffer from poorer diagnostic performance for the detection of recurrent gastric cancer. There are only a few reports using FDG PET/CT to predict response to neoadjuvant or adjuvant chemotherapy. A complete metabolic response seems to be predictive of more favorable prognosis.

‣ microRNAs and cancer metabolism reprogramming: the paradigm of metformin

Pulito, Claudio; Donzelli, Sara; Muti, Paola; Puzzo, Luisa; Strano, Sabrina; Blandino, Giovanni
Fonte: AME Publishing Company Publicador: AME Publishing Company
Tipo: Artigo de Revista Científica
Publicado em /06/2014 Português
Relevância na Pesquisa
46.95445%
Increasing evidence witnesses that cancer metabolism alterations represent a critical hallmark for many types of human tumors. There is a strong need to understand and dissect the molecular mechanisms underlying cancer metabolism to envisage specific biomarkers and underpin critical molecular components that might represent novel therapeutic targets. One challenge, that is the focus of this review, is the reprogramming of the altered metabolism of a cancer cell toward that of un-transformed cell. The anti-hyperglicemic agent, metformin has proven to be effective in reprogramming the metabolism of cancer cells even from those subpopulations endowed with cancer stem like features and very high chemoresistenace to conventional anticancer treatments. A functional interplay involving selective modulation of microRNAs (miRNAs) takes place along the anticancer metabolic effects exerted by metformin. The implications of this interplay will be also discussed in this review.

‣ Cancer Metabolism: Strategic Diversion from Targeting Cancer Drivers to Targeting Cancer Suppliers

Kim, Soo-Youl
Fonte: The Korean Society of Applied Pharmacology Publicador: The Korean Society of Applied Pharmacology
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
46.983936%
Drug development groups are close to discovering another pot of gold-a therapeutic target-similar to the success of imatinib (Gleevec) in the field of cancer biology. Modern molecular biology has improved cancer therapy through the identification of more pharmaceutically viable targets, and yet major problems and risks associated with late-phase cancer therapy remain. Presently, a growing number of reports have initiated a discussion about the benefits of metabolic regulation in cancers. The Warburg effect, a great discovery approximately 70 years ago, addresses the “universality” of cancer characteristics. For instance, most cancer cells prefer aerobic glycolysis instead of mitochondrial respiration. Recently, cancer metabolism has been explained not only by metabolites but also through modern molecular and chemical biological techniques. Scientists are seeking context-dependent universality among cancer types according to metabolic and enzymatic pathway signatures. This review presents current cancer metabolism studies and discusses future directions in cancer therapy targeting bio-energetics, bio-anabolism, and autophagy, emphasizing the important contribution of cancer metabolism in cancer therapy.

‣ Modeling cancer metabolism on a genome scale

Yizhak, Keren; Chaneton, Barbara; Gottlieb, Eyal; Ruppin, Eytan
Fonte: John Wiley & Sons, Ltd Publicador: John Wiley & Sons, Ltd
Tipo: Artigo de Revista Científica
Publicado em 30/06/2015 Português
Relevância na Pesquisa
47.01253%
Cancer cells have fundamentally altered cellular metabolism that is associated with their tumorigenicity and malignancy. In addition to the widely studied Warburg effect, several new key metabolic alterations in cancer have been established over the last decade, leading to the recognition that altered tumor metabolism is one of the hallmarks of cancer. Deciphering the full scope and functional implications of the dysregulated metabolism in cancer requires both the advancement of a variety of omics measurements and the advancement of computational approaches for the analysis and contextualization of the accumulated data. Encouragingly, while the metabolic network is highly interconnected and complex, it is at the same time probably the best characterized cellular network. Following, this review discusses the challenges that genome-scale modeling of cancer metabolism has been facing. We survey several recent studies demonstrating the first strides that have been done, testifying to the value of this approach in portraying a network-level view of the cancer metabolism and in identifying novel drug targets and biomarkers. Finally, we outline a few new steps that may further advance this field.

‣ Ovarian Cancer Metabolism: Effect of Anoikis Condition and Nitric Oxide on Ovarian Cancer Metabolism, and Effect of Metabolites on Ovarian Cancer Migration

Caneba, Christine
Fonte: Universidade Rice Publicador: Universidade Rice
Português
Relevância na Pesquisa
67.154575%
Ovarian cancer remains the most lethal gynecological malignancy worldwide, with most of the disease detected at later stages. Elucidating pathways based on upregulation of proteins and genes involved in the development and progression of ovarian cancer is underway. However, understanding of the metabolic regulation and changes in metabolism involved in ovarian cancer is lacking, and this understanding could lead to development of therapies for ovarian cancer. In order for ovarian cancer cells to metastasize, they must be able to survive deprived of extracellular matrix attachment in the peritoneal cavity. In the first part of this thesis, the effect of cell detachment on the metabolism of highly-invasive and less-invasive ovarian cancer cells was explored by employing culture methods that induced cell detachment. Experiments were designed to collect media from the cells for metabolic analysis to gain insight into changes in the glycolytic and oxidative phosphorylation pathways. Results showed that oxidative phosphorylation was higher for highly-invasive versus less-invasive ovarian cancer cells in detachment. It was also observed that highly-invasive ovarian cancer cells consumed more pyruvate than less-invasive ovarian cancer cells...

‣ Unraveling cancer metabolism through flux analysis and metabolic engineering

Tavares, Ludgero Canário
Fonte: Universidade de Coimbra Publicador: Universidade de Coimbra
Tipo: Tese de Doutorado
Português
Relevância na Pesquisa
47.019243%
Cancer therapies have significantly improved over the last decades. However, some cancers, such as lung cancer, still have very poor outcomes and high mortality rates, even when proper treatment is applied. New treatment strategies must be adopted, which will require better understanding of cancer mechanisms. For that purpose, three human lung cell lines were used in this study, MRC-5, a human lung fibroblast cell line and A549, H1299, two human non-small lung cancer cells. The metabolic remodeling occurring in carcinogenesis cells is firmly established. However, to understand the connection between the cellular metabolic profile and carcinogenesis, an accurate measurement of metabolic fluxes is required. In order to quantify the fluxes in these metabolic pathways, stable isotopes tracers and nuclear magnetic resonance techniques were employed. For the quantification of carbon intermediary metabolism cells were grown in 13C labelled glucose while for de novo lipogenesis (DNL) assessment 2H2O was supplemented to the culture media. To better understand and characterize cellular bioenergetics, mitochondrial membrane potential, oxygen consumption, and energy charge were also assessed. Also, recent reports describe a reductive carboxylation operated by isocitrate dehydrogenase (IDH)...

‣ Metabolic shifts toward glutamine regulate tumor growth, invasion and bioenergetics in ovarian cancer

Yang, Lifeng; Moss, Tyler; Mangala, Lingegowda S.; Marini, Juan; Zhao, Hongyun; Wahlig, Stephen; Armaiz-Pena, Guillermo; Jiang, Dahai; Achreja, Abhinav; Win, Julia; Roopaimoole, Rajesha; Rodriguez-Aguayo, Cristian; Mercado-Uribe, Imelda; Lopez-Berestein,
Fonte: Universidade Rice Publicador: Universidade Rice
Tipo: Journal article; Text; publisher version
Português
Relevância na Pesquisa
56.73906%
Glutamine can play a critical role in cellular growth in multiple cancers. Glutamine‐addicted cancer cells are dependent on glutamine for viability, and their metabolism is reprogrammed for glutamine utilization through the tricarboxylic acid (TCA) cycle. Here, we have uncovered a missing link between cancer invasiveness and glutamine dependence. Using isotope tracer and bioenergetic analysis, we found that low‐invasive ovarian cancer (OVCA) cells are glutamine independent, whereas high‐invasive OVCA cells are markedly glutamine dependent. Consistent with our findings, OVCA patients’ microarray data suggest that glutaminolysis correlates with poor survival. Notably, the ratio of gene expression associated with glutamine anabolism versus catabolism has emerged as a novel biomarker for patient prognosis. Significantly, we found that glutamine regulates the activation of STAT3, a mediator of signaling pathways which regulates cancer hallmarks in invasive OVCA cells. Our findings suggest that a combined approach of targeting high‐invasive OVCA cells by blocking glutamine's entry into the TCA cycle, along with targeting low‐invasive OVCA cells by inhibiting glutamine synthesis and STAT3 may lead to potential therapeutic approaches for treating OVCAs.

‣ Metabolism and brain cancer

Marie, Suely Kazue Nagahashi; Shinjo, Sueli Mieko Oba
Fonte: Universidade de São Paulo. Faculdade de Medicina Publicador: Universidade de São Paulo. Faculdade de Medicina
Tipo: info:eu-repo/semantics/article; info:eu-repo/semantics/publishedVersion; ; ; ; ; ; Formato: application/pdf
Publicado em 01/01/2011 Português
Relevância na Pesquisa
46.965522%
Cellular energy metabolism is one of the main processes affected during the transition from normal to cancer cells, and it is a crucial determinant of cell proliferation or cell death. As a support for rapid proliferation, cancer cells choose to use glycolysis even in the presence of oxygen (Warburg effect) to fuel macromolecules for the synthesis of nucleotides, fatty acids, and amino acids for the accelerated mitosis, rather than fuel the tricarboxylic acid cycle and oxidative phosphorylation. Mitochondria biogenesis is also reprogrammed in cancer cells, and the destiny of those cells is determined by the balance between energy and macromolecule supplies, and the efficiency of buffering of the cumulative radical oxygen species. In glioblastoma, the most frequent and malignant adult brain tumor, a metabolic shift toward aerobic glycolysis is observed, with regulation by well known genes as integrants of oncogenic pathways such as phosphoinositide 3-kinase/protein kinase, MYC, and hypoxia regulated gene as hypoxia induced factor 1. The expression profile of a set of genes coding for glycolysis and the tricarboxylic acid cycle in glioblastoma cases confirms this metabolic switch. An understanding of how the main metabolic pathways are modified by cancer cells and the interactions between oncogenes and tumor suppressor genes with these pathways may enlighten new strategies in cancer therapy. In the present review...

‣ Metabolic Targeting of Cancer Cells: Two Molecular Mechanisms Involving Glucose Metabolism

Quinones, Quintin Jose
Fonte: Universidade Duke Publicador: Universidade Duke
Tipo: Dissertação Formato: 4114052 bytes; application/pdf
Publicado em //2009 Português
Relevância na Pesquisa
46.97259%

Selective therapeutic targeting of tumors requires identification of differences between the homeostatic requirements of cancer and host cells. One such difference is the manner in which cancer cells acquire energy. Cancer cells often grow in an environment of local hypoxia; under these conditions tumor cells depend on glycolysis for energy, but are unable to perform oxidative phosphorylation. Many tumor cells, despite normoxic conditions, continue to perform glycolysis without oxidative phosphorylation. The net result of glycolysis without oxidative phosphorylation is twofold: the need to consume a greater amount of glucose than a non-cancerous host cell, and the burden of increased intracellular lactic acid. The proteins responsible for the transport of lactic acid in and out of cells are known as the monocarboxylate transporters (MCTs). Monocarboxylate Transporter 1 (MCT1) and Monocarboxylate Transporter 4 (MCT4) are the MCTs that play a major role in the transport of lactic acid. Tumor cells depend on MCT1 and MCT4 activity to excrete excess intracellular lactic acid to maintain neutral intracellular pH and homeostasis. Using human neuroblastoma and prostate cancer cell lines this work demonstrates that tumor cells can be selectively targeted tumor under conditions of hypoxia or acidosis in vitro with the drug lonidamine...

‣ Lactate Metabolism in Cancer Cell Lines

Kennedy, Kelly Marie
Fonte: Universidade Duke Publicador: Universidade Duke
Tipo: Dissertação
Publicado em //2013 Português
Relevância na Pesquisa
47.16281%

Pathophysiologic lactate accumulation is characteristic of solid tumors and has been associated with metastases and poor overall survival in cancer patients. In recent years, there has been a resurgence of interest in tumor lactate metabolism. In the past, our group has shown that lactate can be used as a fuel in some cancer cell lines; however, survival responses to exogenous lactate alone are not well-described. We hypothesized that lactate utilization and cellular responses to exogenous lactate were varied and dynamic, dependent upon factors such as lactate concentration, duration of lactate exposure, and of expression of the lactate transporter, monocarboxylate transporter 1 (MCT1). We hypothesized that pharmacological inhibition of MCT1 with a small molecule, competitive MCT1 inhibitor, α-cyano-4-hydroxycinnamic acid (CHC), could elicit cancer cell death in high lactate conditions typical of that seen in breast cancer.

My work focused on defining: 1. Lactate levels in locally advanced breast cancer (LABC); 2. Lactate uptake and catabolism in a variety of cancer cell lines; 3. The effect of exogenous lactate on cancer cell survival; 4. Whether the lactate-transporters, MCT1 and MCT4 can be used as markers of cycling hypoxia.

Lactate levels in LABC biopsies were assessed ex vivo by bioluminescence. NMR techniques were employed extensively to determine metabolites generated from 13C-labeled lactate. Cell viability in response to extracellular lactate ( ± glucose and ± CHC) was measured with Annexin V / 7-AAD staining to assess acute survival responses and clonogenic assays to evaluate long-term colony forming ability after lactate treatment. MCT1 and MCT4 protein expression was evaluated in cancer cell lines with Western blots after exposure to chronic or cycling hypoxia. Immunofluorescence was employed to assess MCT1 and MCT4 expression in head and neck cancer biopsies...

‣ Examining Glucose Metabolism in Survival and Proliferation of B Cell Derived Leukemia

Liu, Tingyu
Fonte: Universidade Duke Publicador: Universidade Duke
Tipo: Dissertação
Publicado em //2014 Português
Relevância na Pesquisa
47.167383%

It has been long known that many types of cancers have high metabolic requirements and use reprogrammed metabolism to support cellular activities. The first identified metabolic alteration in cancer cells was elevated glucose uptake, glycolysis activity and lactate production even in the presence of oxygen. This metabolic program, termed aerobic glycolysis or the Warburg effect, provides cells with energy as well as biosynthetic substrates to sustain cell survival and rapid cell proliferation. Cancer metabolism is closely linked to genetic mutations and oncogenic signaling pathways, such as PI3K/Akt, cMyc and HIF pathways. These oncogenic signals can direct metabolic reprogramming while changes in metabolic status can regulate activities of these signaling pathways in turn. In addition to glucose, later studies also found utilization of alternate nutrients in cancer cells, including glutamine and lipids. Glutamine is the second major metabolic fuel and can be converted to various substrates to support cell bioenergetics needs and biosynthetic reactions. Usage of metabolic fuels in cancer cells, however, is variable. While certain cancers display addiction to one type of nutrient, others are capable of using multiple nutrients.

The unique metabolic features of cancer cells raise the possibility of targeting metabolism as a novel therapeutic approach for cancer treatment. Using pharmacological inhibitors...