The role of glutamine metabolism in castration-resistant prostate cancer / 亚洲男科学杂志(英文版)

Reprogramming of metabolism is a hallmark of tumors, which has been explored for therapeutic purposes. Prostate cancer (PCa), particularly advanced and therapy-resistant PCa, displays unique metabolic properties. Targeting metabolic vulnerabilities in PCa may benefit patients who have exhausted currently available treatment options and improve clinical outcomes. Among the many nutrients, glutamine has been shown to play a central role in the metabolic reprogramming of advanced PCa. In addition to amino acid metabolism, glutamine is also widely involved in the synthesis of other macromolecules and biomasses. Targeting glutamine metabolic network by maximally inhibiting glutamine utilization in tumor cells may significantly add to treatment options for many patients. This review summarizes the metabolic landscape of PCa, with a particular focus on recent studies of how glutamine metabolism alterations affect therapeutic resistance and disease progression of PCa, and suggests novel therapeutic strategies.

Role of metabolic reprogramming in drug resistance to epidermal growth factor tyrosine kinase inhibitors in non-small cell lung cancer / 中南大学学报(医学版)

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) can effectively inhibit the growth of EGFR-dependent mutant non-small cell lung cancer (NSCLC). Unfortunately, NSCLC patients often develop severe drug resistance after long-term EGFR-TKI treatment. Studies have shown that the disorder of energy metabolism in tumor cells can induce EGFR-TKI resistance. Due to the drug action, gene mutation and other factors, tumor cells undergo metabolic reprogramming, which increases the metabolic rate and intensity of tumor cells, promotes the intake and synthesis of nutrients (such as sugar, fat and glutamine), forms a microenvironment conducive to tumor growth, enhances the bypass activation, phenotype transformation and abnormal proliferation of tumor cells, and inhibits the activity of immune cells and apoptosis of tumor cells, ultimately leading to drug resistance of tumor cells to EGFR-TKI. Therefore, targeting energy metabolism of NSCLC may be a potential way to alleviate TKI resistance.

Proteins moonlighting in tumor metabolism and epigenetics / 医学前沿

Cancer development is a complicated process controlled by the interplay of multiple signaling pathways and restrained by oxygen and nutrient accessibility in the tumor microenvironment. High plasticity in using diverse nutrients to adapt to metabolic stress is one of the hallmarks of cancer cells. To respond to nutrient stress and to meet the requirements for rapid cell proliferation, cancer cells reprogram metabolic pathways to take up more glucose and coordinate the production of energy and intermediates for biosynthesis. Such actions involve gene expression and activity regulation by the moonlighting function of oncoproteins and metabolic enzymes. The signal - moonlighting protein - metabolism axis facilitates the adaptation of tumor cells under varying environment conditions and can be therapeutically targeted for cancer treatment.

Mecanismos moleculares emergentes y células madre leucémicas en la quimiorresistencia de tumores hematológicos / Emerging molecular mechanisms and leukemic stem cells in chemoresistance of hematologic tumors

Resumen Las leucemias agudas son trastornos clonales originados a partir de células hematopoyéticas primitivas multipotenciales que se caracterizan por la proliferación, diferenciación y maduración aberrante de células progenitoras leucémicas como resultado de varios eventos genéticos y epigenéticos. Aunque en la actualidad se han implementado diferentes esquemas de quimioterapia para mejorar el pronóstico de los pacientes, las leucemias agudas representan una malignidad hematológica con pobre desenlace clínico y bajas tasas de supervivencia en pacientes pediátricos y adultos Colombianos. Uno de los principales obstáculos para el tratamiento exitoso del cáncer es el desarrollo de resistencia a los medicamentos durante la quimioterapia y la enfermedad recurrente. En el estudio de la biología de las células tumorales, se reconoce que los diversos cambios oncogénicos y la evolución clonal que sufren las células tumorales, son cambios biológicos que les confieren mecanismos de resistencia a la quimioterapia convencional, que a su vez se traducen en un incremento en las tasas de mortalidad y/o el aumento de recaídas en los pacientes que padecen esta enfermedad. Por lo tanto, el estudio de los mecanismos empleados por las células leucémicas para escapar del efecto citotóxico del tratamiento empleado para combatir la enfermedad es un objetivo primordial de la investigación en cáncer. En este contexto, el objetivo del presente artículo es hacer una revisión detallada de los avances más recientes en la comprensión de los mecanismos involucrados en la resistencia tumoral en leucemias, haciendo especial énfasis en el papel que desempeñan las células madre leucémicas y el metabolismo tumoral en la quimiorresistencia de este grupo de enfermedades. El conocimiento de los mecanismos de resistencia tumoral, así como el entendimiento detallado de las interacciones entre las células normales y leucémicas en el microambiente de la médula ósea, son prometedores blancos terapéuticos de las leucemias agudas.

Abstract Acute leukemias (AL) are clonal disorders originated from multi-potent immature hematopoietic cells and are characterized by aberrant proliferation, differentiation and maturation of leukemic progenitor cells as a result of multiple genetic and epigenetic events. Even though different chemotherapy regimens have been implemented to improve patient prognostic, acute leukemias represent a hematological malignancy with poor clinical outcome and low survival rates in pediatric and adult patients in Colombia. One of the main obstacles to the success of cancer treatment is the development of drug resistance during chemotherapy and the recurrent disease. In the study of tumor cells biology, it is now known that clonal evolution and oncogenic changes of tumor cells are biological properties that confer resistance mechanisms to conventional chemotherapy, which in turn translate into an increased mortality rate and/or an increased risk of relapse in leukemia patients. Therefore, the study of mechanisms that leukemic cells employ to avoid the cytotoxic effects of some chemotherapeutics is a main objective of cancer research. In this context, the objective of the current paper is to give a detailed information about recent advances in mechanisms involved in leukemic resistance, with special emphasis on the role of leukemic stem cells theory and tumor metabolism.

Research progress on the regulation of tumor metabolism, tumor immunotherapy and new analytical methods / 药学学报

In order to achieve rapid proliferation and adapt to the complex microenvironment, tumor cells have dominant characteristics such as unique metabolic patterns and the ability to escape from immunoregulation. Tumor cells reprogram multiple metabolic pathways to promote immune escape, which impacts tumor diagnosis, treatment and prognosis. Based on the effect of metabolic changes on tumor immune escape and its molecular mechanism, metabolic regulation provides new approaches to enhance immunotherapy. We review recent advances in tumor immuno-escape and immunotherapy based on metabolic regulation. Cutting-edge analytical techniques and methods for tumor metabolism research such as metabolomics, mass spectrometry imaging-based spatially-resolved metabolomics and metabolic flow analysis are also discussed.

Research progress on the role of autophagy in cancer-associated fibroblasts / 中国肿瘤生物治疗杂志

@#Cancer-associated fibroblasts (CAFs) are one of the predominant stromal cells that constitute the tumor microenvironment, and play an essential role in tumor growth, metastasis, chemoresistance and tumor immunity. Autophagy is a cellular process through which cells degrade products in the metabolic process and reuse them to respond to environmental stress. Autophagy is important for tumor initiation, progression and response to therapy, as it connects cellular homeostasis with the extracellular environment that affects immunity and metabolism. This review, by introducing the role of autophagy in CAFs and its regulatory mechanism, summarizes the research progress on studies of autophagy in CAFs and tumor metabolism, progression, metastasis and resistance to therapy.

Formation mechanism of tumor acidic microenvironment and its effects on tumor progression / 肿瘤

Tumor microenvironment plays an important role in the formation and development of tumors, and the acidity is one of the remarkable features of tumor microenvironment. Due to excessive proliferation of tumor cells and abnormal structure of tumor blood vessels, the tumor tissues are usually in a hypoxia state, leading to changes in the metabolic processes of tumor cells. Compared with the normal tissues which mainly rely on aerobic oxidation to obtain energy, the metabolism of tumor cells dominatingly depends on the anaerobic glycolysis. Therefore, the lactate acid produced by glycolysis and the carbon dioxide produced by respiration together result in the acidification of tumor microenvironment (TME), and affects many aspects of tumorigenesis and development. This review focuses on the formation mechanism of tumor acidic microenvironment and its impacts on tumor progression, including tumor immunity, invasion, autophagy and resistance to anti-cancer treatment.

Research progress of tumor immune and tumor metabolic drug targets / 药学学报

The occurrence and development of tumors are closely related to the tumor microenvironment. Among them, tumor immune microenvironment and tumor metabolic microenvironment play important roles in tumor. Tumor immunotherapy is a way to kill tumor cells by activating the body's immune system. Tumor immunotherapy has shown good therapeutic effects in a variety of solid tumors. In recent years, significant progress has been made in tumor immunotherapy. The Warburg effect indicates that tumor cells use aerobic glycolysis to acquire energy. In the tumor, the energy metabolism pathway is abnormal, and the tumor microenvironment can induce the reprogramming of tumor cell metabolism. Therefore, targeting tumor metabolism is also of great significance for tumor treatment. In this paper, we reviewed the research progress of drug targets related to tumor immunology and tumor metabolism in recent years, as well as the progress of drug development.

Imaging Cancer Metabolism

It is widely accepted that altered metabolism contributes to cancer growth and has been described as a hallmark of cancer. Our view and understanding of cancer metabolism has expanded at a rapid pace, however, there remains a need to study metabolic dependencies of human cancer in vivo. Recent studies have sought to utilize multi-modality imaging (MMI) techniques in order to build a more detailed and comprehensive understanding of cancer metabolism. MMI combines several in vivo techniques that can provide complementary information related to cancer metabolism. We describe several non-invasive imaging techniques that provide both anatomical and functional information related to tumor metabolism. These imaging modalities include: positron emission tomography (PET), computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS) that uses hyperpolarized probes and optical imaging utilizing bioluminescence and quantification of light emitted. We describe how these imaging modalities can be combined with mass spectrometry and quantitative immunochemistry to obtain more complete picture of cancer metabolism. In vivo studies of tumor metabolism are emerging in the field and represent an important component to our understanding of how metabolism shapes and defines cancer initiation, progression and response to treatment. In this review we describe in vivo based studies of cancer metabolism that have taken advantage of MMI in both pre-clinical and clinical studies. MMI promises to advance our understanding of cancer metabolism in both basic research and clinical settings with the ultimate goal of improving detection, diagnosis and treatment of cancer patients.

Expression, functions and regulation of PKM2 in tumor cells / 复旦学报（医学版）

M2 type of pyruvate kinase (PKM2) is one of the most important regulatory molecules in glycolysis,which at high level is a major feature of tumor cells.Besides,PKM2 also regulates gene transcription and cell cycle,promoting the formation,invasion and migration of tumors.Meanwhile,PKM2 can beregulated by many transcription factors,oncogene proteins,miRNA and intermediate metabolites.Extensive studies indicated that PKM2 plays an important role in the developmental tumor.In view of the significance of PKM2 in tumor cells,it holds promise for diagnosis and treatment benefits.

Research progress in metabolic targets for cancer therapy / 中国药理学与毒理学杂志

Cancer cells can change metabolic pathways, including glycolysis and glutamine metabolism, and produce the raw materials needed for rapid proliferation and survival. Therefore, research on metabolic pathways of cancer cells might help find the targets of cancer therapy. In this review, we outlined the metabolic features of aerobic glycolysis, glutamine metabolism and (tricarboxylic acid) TCA cycle in cancer. We also described metabolic targets for cancer therapy and therapeutic agents for the corresponding targets in these metabolic pathways, and finally discussed some of the challenges related to tumor metabolism as a therapeutic target in cancer therapy.

Recent Proceedings in Research of Tumor-associated Disorders of Glucose Metabolism / 中山大学学报(医学科学版)

Metabolic rearrangement is a typical hallmark of cancer cells ,especially the disorders in glucose metabolism. Normal cells rely on the steps of oxidative phosphorylation within the mitochondria to metabolize glucose and yield energy upon enough oxygen ,yet turning to glycolysis in the absence of oxygen . Nevertheless ,tumor cells exhibit high levels of glycolytic flux in different environments ,due to the requirement of malignant proliferation. This phenomenon was named as the Warburg effect ,the initiation of which is driven by multiple mechanisms ,including the influence of tumor microenvironment ,the activa?tion of tumor-promoting signaling pathways ,and the aberrant levels of metabolic enzymes. Moreover ,our recent findings sug?gest that inhibition of gluconeogenesis ,the general reversal of glycolysis ,would further promote the Warburg effect and tumor progression.

The work-in-progress in biological cancer therapy / 医学研究生学报

Novel and efficient therapeutic modalities are urgently needed for cancer patients .We focused on biological therapies including oncolytic virotherapy and immune therapy against cancer .In the study of oncolytic virotherapy , we have identified the crosstalk between virus-induced mitophagy and retinoic acid inducible gene I (RIG-I)-like receptors signaling.Importantly, we find that cell necrosis rather than apoptosis ( as supposed by previous studies ) contributes dominantly to oncolysis of measles virus Edmon-strain in cancer.Furthermore, we have clarified the role of mitophagy in switching cell death from apoptosis to necrosis .These novel findings are important for further improvement of oncolyticvirotherapy .5′-Triphosphate RNA ( ppp-RNA) is a specific ligand of the pat-tern recognition receptor retinoic acid-inducible gene I ( RIG-I) .By combining immune activation and specific gene silencing , we have designed three anticancer ppp-siRNAs targeting TGF-β1 , GLS1 and VEGF , respectively , and we find that these ppp-siRNAs possess potent antitumor efficacies both in vitro and in vivo .In addition , we have also utilized nanomaterials to treat cancers .Next, we want and try to block the immune escape of cancer by targeting immune checkpoints .

Effects of XBP1 on glioma cell viability and glycolysis under hypoxia / 中国肿瘤临床

Objective:To determine the effect of hypoxic stress on glioma cell XBP1 expression, the relationship between XBP1 expres-sion and sugar metabolism, the influence of XBP1 repression on the survival rate of glioma cells under normoxia and hypoxia, and the influence of XBP1 on glioma cell glycolysis. Methods:We tested XBP1 activation in human glioma cell lines cultured under normoxia and hypoxia. XBP1 expression was repressed with siRNA technology. Cells were treated with oxidative phosphorylation inhibitor. We then detected the variation in cell apoptosis, sugar metabolism mode, and cell apoptosis and glycolysis products under normoxia and hypoxia. Results:XBP1 activation increased under hypoxia. Silencing XBP1 expression reduced glioma cell survival level, ATP and lactic acid production, and glucose consumption under hypoxia. After inhibiting cell oxidative phosphorylation, XBP1 repression significantly reduced the survival level of glioma cells. Conclusion:Hypoxia can activate XBP1 in glioma cells. Under hypoxia, XBP1 silencing de-presses cell activity and glycolysis. Glycolysis of glioma cells under hypoxia depends on XBP1 activation.

Research progress on relationship between glucose transporter 1 and tumor energy metabolism / 中国药理学通报

The study on tumor metabolism has been gradually be-come a hot spot in recent years .A lot of proteins involved in the regulation of tumor metabolism especially the glucose transporter protein 1(GLUT1).As a key regulatory factor mediating energy metabolism within tumor cells , GLUT1 can regulate the glucose intake and maintain the basic level of metabolism in tumor cells . More importantly, the abnormal expression of GLUT1 was asso-ciated with many kinds of tumors , of which GLUT1 was used to meet the energy requirement for the fast growth of tumor .Thus GLUT1 also played a crucial role in growth , differentiation and metastasis of tumor cells and prognosis of tumors .Meanwhile , as three-dimensional crystal structure of GLUT 1 was determined , it is possible to design the small molecular inhibitors of GLUT 1, which can realize “starve to death” tumor cells.GLUT1 can be a particularly attractive target for tumor treatment and interfer-ence.The relationship between abnormal expression of GLUT 1 protein and tumor metabolism was reviewed . Moreover , the mechanism of tumor metabolism regulated by GLUT 1 protein ex-pression and treatment of cancers were discussed , which may provide references for future research and clinical treatment .

Caracterização bioquímica e celular da glutaminase isoforma Kidney-type com seus parceiros de interação / Biochemical and cellular characterization of Kidney-type glutaminase with their interaction partners

Células tumorais apresentam uma autonomia metabólica aumentada em comparação a células não-transformadas, incorporando nutrientes e metabolizando-os através de vias que suportam o seu crescimento e proliferação. O foco deste trabalho foi a enzima glutaminase, a qual processa glutamina em glutamato para posterior produção de alfa-cetoglutarato pela enzima glutamato desidrogenase, reabastecendo o ciclo do TCA e suportando seu funcionamento e geração de metabólitos essenciais para a síntese de macromoléculas. O gene GLS1 codifica para as isoformas glutaminase kidney-type (KGA) e glutaminase C (GAC). Estas proteínas apresentam outros domínios além do catalítico, e, no caso da KGA, repetições do tipo ankirin, sabidamente envolvidas em contatos proteínas-proteínas. Os objetivos deste projeto foram de encontrar parceiros de interação para a glutaminase kidney-type (KGA) e avaliar o impacto desta interação para o metabolismo tumoral. Um candidato inicialmente avaliado, a Aldolase A, não foi confirmado como parceiro de interação. Outro candidato, a BNIP-H, apesar de ter sido mostrado interagir com a KGA em células nervosas, não mostrou indícios de interação com a KGA em linhagem de células de câncer de mama. Por fim, estudos de duplo-híbrido em levedura revelaram o receptor nuclear PPARγ (Peroxisome proliferator-activated receptor gamma) como forte candidato a parceiro de interação. Realizou-se um mapeamento dos domínios responsáveis pela interação entre estas duas proteínas, também por duplo híbrido, tendo sido identificado o domínio LBD da proteína PPARγ como envolvido na interação. Mesmo estudos realizados com fragmento da KGA, apesar de incompletos, mostraram que a interação não ocorre pelo domínio carboxi-terminal da enzima. Ensaios de anisotropia de fluorescência com as proteínas KGA e PPARγ purificadas indicaram que a interação é favorecida pela presença do produto da reação glutaminolítica, glutamato, e apresenta um Kd de 4,6 ± 0,5 μM...

Tumor cells have an increased metabolic autonomy compared to non-transformed cells, metabolizing nutrients and incorporating them through pathways that support cell growth and proliferation. The focus of this study was the glutaminase enzyme, which processes glutamine to glutamate for subsequent production of alpha-ketoglutarate, by the glutamate dehydrogenase enzyme, replenishing TCA cycle and bearing its function and the generation of metabolites essential for the synthesis of macromolecules. The gene GLS1 codes for the isoforms kidney-type glutaminase (KGA) and glutaminase C (GAC). These proteins exhibit other domains besides the catalytic, and in the case of KGA, ankirin repeats, known to be involved in protein-protein contacts. The goal of this project was to investigate potential interacting partners of KGA and contextualize the interaction within the metabolic demands of tumor cells. A candidate initially evaluated, the Aldolase A, was not confirmed as a partner of interaction. Another candidate, the BNIP-H, despite having been shown to interact with the KGA in nervous cells, showed no evidence of interaction with KGA in one tested breast cancer cell lines. Finally, yeast two-hybrid studies revealed the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) as a strong interaction partner candidate. We mapped the domains responsible for the interaction between these two proteins, also by two-hybrid and identified the LBD domain of PPARγ as involved in the interaction. The same studies with KGA fragments, although incomplete, showed that the interaction did not involve the carboxy-terminal domain of the enzyme. KGA and PPARγ proteins were expressed in E. coli, purified and their interaction was analyzed by pull-down, fluorescence anisotropy, electrophoresis under native conditions, gel filtration chromatography and crosslinking...

New Trend of tumor PET imaging radiopharmaceuticals / 한양의대학술지

Tumor PET imaging with radiopharmaceuticals plays a major role in the understanding of tumor biological information and for diagnosis of tumorswith non-invasive methods. These radiopharmaceuticals can be divided into two categories radiopharmaceuticals for metabolic process imaging and for specific receptor imaging. Most tumor imaging radiopharmaceuticals such as [18F]FDG, [18F]FLT, and [11C]choline can be trapped in tumor cells by specific metabolic processes of each radiopharmaceutical and show an increase in metabolism of tumor regions. Unlike these compounds, the hypoxia imaging adiopharmaceuticals such as [18F]FMISO and [64Cu]ATSM are trapped by oxidative metabolic mechanisms under only hypoxic conditions of tumor cells. For tumor specific receptor imaging, [18F]FES for estrogen receptor positive breast cancer may be used and recent clinical results showed the possibility of evaluating tumor therapy responseby estrogen receptor imaging with [18F]FES. This paper gives an overview of the current status of tumor PET imaging adiopharmaceuticals and the development of new lead compounds as potential radiopharmaceuticals by medicinal chemistry.

Brain Tumors in Which Lactate and Lipid Have Been Detected: A Proton Magnetic Resonance Spectroscopy Study

To determine the spectral pattern of metabolites in 31 brain tumors in which the presence of lipids, lactate and additional intermediary metabolites had been detected, in vivo 1H-MR spectroscopy was performed. Metastasis (n=3), meningioma(n=7), astrocytic tumors of different grades(n=11), postop recurrent tumors(n=2) and other tumors(n=10) were examined using the stimulated echo(STEAM, TE=30ms) or double spin echo technique(PRESS, TE=272ms) with CHESS pulse for water suppression. The detection of lactate in astrocytic tumors correlated with a higher grade of malignancy, and lipid was observed in most glioblastomas. Elevated lactate levels in tumors do not simply originate in the necrotic region, but are related to the high glycolytic activity of adequately perfused, viable neoplastic cells. Lipid signals were detected in high grade, late stage brain tumors, indicating the need for enhanced phospholipid metabolism and membrane degradation, respectively. The absence of lactate and presence of alanine, glutamate/glutamine in most meningiomas distinguished them from schwannomas and other glial tumors. Observation of the spectral pattern of metabolites in brain tumors in which lipid and lactate has been detected might play an important prognostic role in the management and differentiation of metastasis, glial tumors, tumor recurrence, and other non-neoplastic diseases.