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1.
Nat Commun ; 12(1): 5203, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471141

RESUMO

Aurora kinase A (AURKA) has emerged as a drug target for glioblastoma (GBM). However, resistance to therapy remains a critical issue. By integration of transcriptome, chromatin immunoprecipitation sequencing (CHIP-seq), Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq), proteomic and metabolite screening followed by carbon tracing and extracellular flux analyses we show that genetic and pharmacological AURKA inhibition elicits metabolic reprogramming mediated by inhibition of MYC targets and concomitant activation of Peroxisome Proliferator Activated Receptor Alpha (PPARA) signaling. While glycolysis is suppressed by AURKA inhibition, we note an increase in the oxygen consumption rate fueled by enhanced fatty acid oxidation (FAO), which was accompanied by an increase of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α). Combining AURKA inhibitors with inhibitors of FAO extends overall survival in orthotopic GBM PDX models. Taken together, these data suggest that simultaneous targeting of oxidative metabolism and AURKAi might be a potential novel therapy against recalcitrant malignancies.


Assuntos
Aurora Quinase A/genética , Aurora Quinase A/metabolismo , Glioblastoma/genética , Glioblastoma/metabolismo , Efeito Warburg em Oncologia , Linhagem Celular Tumoral , Proliferação de Células , Ácidos Graxos/metabolismo , Glicólise/efeitos dos fármacos , Humanos , PPAR alfa/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteômica , Transdução de Sinais/efeitos dos fármacos , Transcriptoma , Efeito Warburg em Oncologia/efeitos dos fármacos
2.
Int J Mol Sci ; 22(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34361035

RESUMO

B lymphocytes are an indispensable part of the human immune system. They are the effective mediators of adaptive immunity and memory. To accomplish specificity against an antigen, and to establish the related immunologic memory, B cells differentiate through a complicated and strenuous training program that is characterized by multiple drastic genomic modifications. In order to avoid malignant transformation, these events are tightly regulated by multiple checkpoints, the vast majority of them involving bioenergetic alterations. Despite this stringent control program, B cell malignancies are amongst the top ten most common worldwide. In an effort to better understand malignant pathobiology, in this review, we summarize the metabolic swifts that govern normal B cell lymphopoiesis. We also review the existent knowledge regarding malignant metabolism as a means to unravel new research goals and/or therapeutic targets.


Assuntos
Linfócitos B/metabolismo , Linfoma/metabolismo , Linfopoese , Animais , Linfócitos B/citologia , Humanos , Linfoma/patologia , Efeito Warburg em Oncologia
3.
Eur J Med Res ; 26(1): 93, 2021 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-34391478

RESUMO

BACKGROUND: To investigate the value of Dickkopf-related protein 3 (DKK3) on aerobic glycolysis in pancreatic cancer cells, where DKK3-overexpression is used to determine its effects on CD4+ T cells. METHODS: The BxPC-3-DKK3 cell line was constructed, and peripheral blood mononuclear cell (PBMC) was prepared. After isolated the CD4+ T cells, the lactic acid, glucose uptake ability, cellular viability, proliferation, apoptosis, and markers were detected by PCR and western blot, and the concentrations of multiple cytokines were determined using the ELISA method. RESULTS: After co-culture with pancreatic cancer cells overexpressing DKK3, the glucose uptake markedly, proliferation enhanced and apoptosis inhibited in CD4+ T cells. The co-culture model also revealed that DKK3-overexpression promotes the activation and regulates the metabolism and function of CD4+ T cells. CONCLUSIONS: DKK3 alters the metabolic microenvironment of pancreatic cancer cells and further facilitates the function of CD4+ T cells which suggesting that DKK3 may have a therapeutic potential in pancreatic cancer.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Ativação Linfocitária , Neoplasias Pancreáticas/metabolismo , Efeito Warburg em Oncologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Apoptose , Linfócitos T CD4-Positivos/imunologia , Linhagem Celular Tumoral , Células Cultivadas , Humanos
4.
Mol Cell Biol ; 41(10): e0060920, 2021 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-34370552

RESUMO

Triple-negative breast cancer (TNBC) is an aggressive histological subtype of breast cancer. It has been reported that the circular RNA (circRNA) circ-ERBB2 (circBase identifier hsa_circ_0007766) is mainly distributed in the cytoplasm of TNBC cells and promotes the proliferation and invasion of TNBC cells. This study aimed to explore the molecular mechanism of circ-ERBB2 regulating the progression of TNBC. The expression of circ-ERBB2 was detected by quantitative real-time PCR (qRT-PCR). Loss-of-function experiments were performed to investigate the function of circ-ERBB2 in TNBC cells in vitro and in vivo. The regulatory mechanism of circ-ERBB2 was surveyed by bioinformatics analysis and dual-luciferase reporter and RNA immunoprecipitation (RIP) or RNA pulldown assays. We observed that circ-ERBB2 was overexpressed in TNBC, and TNBC patients with high circ-ERBB2 expression levels had a poor prognosis. Functionally, circ-ERBB2 knockdown constrained TNBC growth in vivo, reduced the Warburg effect, accelerated apoptosis, and repressed the proliferation, migration, and invasion of TNBC cells in vitro. Mechanically, circ-ERBB2 sponged microRNA 136-5p (miR-136-5p) to elevate pyruvate dehydrogenase kinase 4 (PDK4) expression. In conclusion, circ-ERBB2 facilitated the Warburg effect and malignancy of TNBC cells by the miR-136-5p/PDK4 pathway, at least in part. This study supports circ-ERBB2 as a prognostic indicator for TNBC.


Assuntos
MicroRNAs/genética , Piruvato Desidrogenase Quinase de Transferência de Acetil/genética , Receptor ErbB-2/genética , Neoplasias de Mama Triplo Negativas/genética , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Piruvato Desidrogenase Quinase de Transferência de Acetil/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , Receptor ErbB-2/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Efeito Warburg em Oncologia
5.
Int J Mol Sci ; 22(12)2021 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-34205414

RESUMO

Citrate plays a central role in cancer cells' metabolism and regulation. Derived from mitochondrial synthesis and/or carboxylation of α-ketoglutarate, it is cleaved by ATP-citrate lyase into acetyl-CoA and oxaloacetate. The rapid turnover of these molecules in proliferative cancer cells maintains a low-level of citrate, precluding its retro-inhibition on glycolytic enzymes. In cancer cells relying on glycolysis, this regulation helps sustain the Warburg effect. In those relying on an oxidative metabolism, fatty acid ß-oxidation sustains a high production of citrate, which is still rapidly converted into acetyl-CoA and oxaloacetate, this latter molecule sustaining nucleotide synthesis and gluconeogenesis. Therefore, citrate levels are rarely high in cancer cells. Resistance of cancer cells to targeted therapies, such as tyrosine kinase inhibitors (TKIs), is frequently sustained by aerobic glycolysis and its key oncogenic drivers, such as Ras and its downstream effectors MAPK/ERK and PI3K/Akt. Remarkably, in preclinical cancer models, the administration of high doses of citrate showed various anti-cancer effects, such as the inhibition of glycolysis, the promotion of cytotoxic drugs sensibility and apoptosis, the neutralization of extracellular acidity, and the inhibition of tumors growth and of key signalling pathways (in particular, the IGF-1R/AKT pathway). Therefore, these preclinical results support the testing of the citrate strategy in clinical trials to counteract key oncogenic drivers sustaining cancer development and resistance to anti-cancer therapies.


Assuntos
Ácido Cítrico/metabolismo , Neoplasias/metabolismo , Animais , Humanos , Oxirredução , Microambiente Tumoral , Efeito Warburg em Oncologia
6.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201062

RESUMO

Cancer is a disorder of cell growth and proliferation, characterized by different metabolic pathways within normal cells. The Warburg effect is a major metabolic process in cancer cells that affects the cellular responses, such as proliferation and apoptosis. Various signaling factors down/upregulate factors of the glycolysis pathway in cancer cells, and these signaling factors are ubiquitinated/deubiquitinated via the ubiquitin-proteasome system (UPS). Depending on the target protein, DUBs act as both an oncoprotein and a tumor suppressor. Since the degradation of tumor suppressors and stabilization of oncoproteins by either negative regulation by E3 ligases or positive regulation of DUBs, respectively, promote tumorigenesis, it is necessary to suppress these DUBs by applying appropriate inhibitors or small molecules. Therefore, we propose that the DUBs and their inhibitors related to the Warburg effect are potential anticancer targets.


Assuntos
Apoptose , Enzimas Desubiquitinantes/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Ubiquitinação , Efeito Warburg em Oncologia , Animais , Humanos
7.
Cell Death Dis ; 12(7): 634, 2021 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-34148062

RESUMO

Signal transducer and activator 5a (STAT5A) is a classical transcription factor that plays pivotal roles in various biological processes, including tumor initiation and progression. A fraction of STAT5A is localized in the mitochondria, but the biological functions of mitochondrial STAT5A remain obscure. Here, we show that STAT5A interacts with pyruvate dehydrogenase complex (PDC), a mitochondrial gatekeeper enzyme connecting two key metabolic pathways, glycolysis and the tricarboxylic acid cycle. Mitochondrial STAT5A disrupts PDC integrity, thereby inhibiting PDC activity and remodeling cellular glycolysis and oxidative phosphorylation. Mitochondrial translocation of STAT5A is increased under hypoxic conditions. This strengthens the Warburg effect in cancer cells and promotes in vitro cell growth under hypoxia and in vivo tumor growth. Our findings indicate distinct pro-oncogenic roles of STAT5A in energy metabolism, which is different from its classical function as a transcription factor.


Assuntos
Mitocôndrias/enzimologia , Complexo Piruvato Desidrogenase/metabolismo , Fator de Transcrição STAT5/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Neoplasias do Colo do Útero/enzimologia , Efeito Warburg em Oncologia , Trifosfato de Adenosina/metabolismo , Animais , Proliferação de Células , Feminino , Glicólise , Células HEK293 , Células HeLa , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/genética , Mitocôndrias/patologia , Fosforilação Oxidativa , Consumo de Oxigênio , Fator de Transcrição STAT5/genética , Carga Tumoral , Hipóxia Tumoral , Microambiente Tumoral , Proteínas Supressoras de Tumor/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia
8.
Nat Commun ; 12(1): 3258, 2021 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-34059679

RESUMO

Autophagy can selectively target protein aggregates, pathogens, and dysfunctional organelles for the lysosomal degradation. Aberrant regulation of autophagy promotes tumorigenesis, while it is far less clear whether and how tumor-specific alterations result in autophagic aberrance. To form a link between aberrant autophagy selectivity and human cancer, we establish a computational pipeline and prioritize 222 potential LIR (LC3-interacting region) motif-associated mutations (LAMs) in 148 proteins. We validate LAMs in multiple proteins including ATG4B, STBD1, EHMT2 and BRAF that impair their interactions with LC3 and autophagy activities. Using a combination of transcriptomic, metabolomic and additional experimental assays, we show that STBD1, a poorly-characterized protein, inhibits tumor growth via modulating glycogen autophagy, while a patient-derived W203C mutation on LIR abolishes its cancer inhibitory function. This work suggests that altered autophagy selectivity is a frequently-used mechanism by cancer cells to survive during various stresses, and provides a framework to discover additional autophagy-related pathways that influence carcinogenesis.


Assuntos
Carcinogênese/genética , Macroautofagia/genética , Proteínas de Membrana/genética , Modelos Genéticos , Proteínas Musculares/genética , Neoplasias/genética , Algoritmos , Animais , Carcinogênese/patologia , Linhagem Celular Tumoral , Simulação por Computador , Análise Mutacional de DNA , Conjuntos de Dados como Assunto , Técnicas de Silenciamento de Genes , Glicogênio/metabolismo , Humanos , Estimativa de Kaplan-Meier , Proteínas de Membrana/metabolismo , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Musculares/metabolismo , Mutação , Neoplasias/mortalidade , Neoplasias/patologia , Via de Pentose Fosfato/genética , Domínios e Motivos de Interação entre Proteínas/genética , Proteoma/genética , RNA-Seq , Análise Serial de Tecidos , Efeito Warburg em Oncologia , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Nat Commun ; 12(1): 3803, 2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-34155197

RESUMO

The adenomatous polyposis coli (APC) is a frequently mutated tumour suppressor gene in cancers. However, whether APC is regulated at the epitranscriptomic level remains elusive. In this study, we analysed TCGA data and separated 200 paired oesophageal squamous cell carcinoma (ESCC) specimens and their adjacent normal tissues and demonstrated that methyltransferase-like 3 (METTL3) is highly expressed in tumour tissues. m6A-RNA immunoprecipitation sequencing revealed that METTL3 upregulates the m6A modification of APC, which recruits YTHDF for APC mRNA degradation. Reduced APC expression increases the expression of ß-catenin and ß-catenin-mediated cyclin D1, c-Myc, and PKM2 expression, thereby leading to enhanced aerobic glycolysis, ESCC cell proliferation, and tumour formation in mice. In addition, downregulated APC expression correlates with upregulated METTL3 expression in human ESCC specimens and poor prognosis in ESCC patients. Our findings reveal a mechanism by which the Wnt/ß-catenin pathway is upregulated in ESCC via METTL3/YTHDF-coupled epitranscriptomal downregulation of APC.


Assuntos
Adenosina/análogos & derivados , Proteínas do Citoesqueleto/genética , Metiltransferases/metabolismo , Proteínas de Ligação a RNA/metabolismo , Adenosina/metabolismo , Animais , Carcinogênese , Proliferação de Células , Proteínas do Citoesqueleto/metabolismo , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Metiltransferases/genética , Camundongos , Prognóstico , RNA Mensageiro/metabolismo , Efeito Warburg em Oncologia , Via de Sinalização Wnt , beta Catenina/genética , beta Catenina/metabolismo
10.
Cancer Sci ; 112(9): 3822-3834, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34181805

RESUMO

Bladder cancer is the 10th most common cancer worldwide. For muscle-invasive bladder cancer (MIBC), treatment includes radical cystectomy, radiotherapy, and chemotherapy; however, the outcome is generally poor. For non-muscle-invasive bladder cancer (NMIBC), tumor recurrence is common. There is an urgent need for more effective and less harmful therapeutic approaches. Here, bladder cancer cell metabolic reprogramming to rely on aerobic glycolysis (the Warburg effect) and expression of associated molecular therapeutic targets by bladder cancer cells of different stages and grades, and in freshly resected clinical tissue, is investigated. Importantly, analyses indicate that the Warburg effect is a feature of both NMIBCs and MIBCs. In two in vitro inducible epithelial-mesenchymal transition (EMT) bladder cancer models, EMT stimulation correlated with increased lactate production, the end product of aerobic glycolysis. Protein levels of lactate dehydrogenase A (LDH-A), which promotes pyruvate enzymatic reduction to lactate, were higher in most bladder cancer cell lines (compared with LDH-B, which catalyzes the reverse reaction), but the levels did not closely correlate with aerobic glycolysis rates. Although LDH-A is expressed in normal urothelial cells, LDH-A knockdown by RNAi selectively induced urothelial cancer cell apoptotic death, whereas normal cells were unaffected-identifying LDH-A as a cancer-selective therapeutic target for bladder cancers. LDH-A and other potential therapeutic targets (MCT4 and GLUT1) were expressed in patient clinical specimens; however, positive staining varied in different areas of sections and with distance from a blood vessel. This intratumoral heterogeneity has important therapeutic implications and indicates the possibility of tumor cell metabolic coupling.


Assuntos
L-Lactato Desidrogenase/metabolismo , Ácido Láctico/biossíntese , Transcriptoma , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo , Efeito Warburg em Oncologia , Apoptose/genética , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/genética , Técnicas de Silenciamento de Genes , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , L-Lactato Desidrogenase/genética , Terapia de Alvo Molecular/métodos , Estadiamento de Neoplasias , Interferência de RNA , Sirtuína 1/genética , Sirtuína 1/metabolismo , Transfecção , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Efeito Warburg em Oncologia/efeitos dos fármacos
11.
Mutat Res Rev Mutat Res ; 787: 108366, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34083056

RESUMO

Breast cancer (BC) is a heterogeneous cancer with multiple subtypes affecting women worldwide. Triple-negative breast cancer (TNBC) is a prominent subtype of BC with poor prognosis and an aggressive phenotype. Recent understanding of metabolic reprogramming supports its role in the growth of cancer cells and their adaptation to their microenvironment. The Warburg effect is characterized by the shift from oxidative to reductive metabolism and external secretion of lactate. The Warburg effect prevents the use of the required pyruvate in the tricarboxylic acid (TCA) cycle progressing through pyruvate dehydrogenase inactivation. Therefore, it is a major regulatory mechanism to promote glycolysis and disrupt the TCA cycle. Glutamine (Gln) can supply the complementary energy for cancer cells. Additionally, it is the main substrate to support bioenergetics and biosynthetic activities in cancer cells and plays a vital role in a wide array of other processes such as ferroptosis. Thus, the switching of glucose to Gln in the TCA cycle toward reductive Gln metabolism is carried out by hypoxia-inducible factors (HIFs) conducted through the Warburg effect. The literature suggests that the addiction of TNBC to Gln could facilitate the proliferation and invasiveness of these cancers. Thus, Gln metabolism inhibitors, such as CB-839, could be applied to manage the carcinogenic properties of TNBC. Such inhibitors, along with conventional chemotherapy agents, can potentially improve the efficiency and efficacy of TNBC treatment. In this review, we discuss the associations between glucose and Gln metabolism and control of cancer cell growth from the perspective that Gln metabolism inhibitors could improve the current chemotherapy drug effects.


Assuntos
Glutamina/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Apoptose/fisiologia , Ferroptose/fisiologia , Humanos , Efeito Warburg em Oncologia
12.
Biochim Biophys Acta Rev Cancer ; 1876(1): 188563, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33971276

RESUMO

Epithelial ovarian cancer, the most lethal gynecological malignancy, is diagnosed at advanced stage, recurs and displays chemoresistance to standard chemotherapeutic regimen of taxane/platinum drugs. Despite development of recent therapeutic approaches including poly-ADP ribose polymerase inhibitors, this fatal disease is diagnosed at advanced stage and heralds strategies for early detection and improved treatment. Recent literature suggests that high propensity of ovarian cancer cells to consume and metabolize glucose via glycolysis even in the presence of oxygen (the 'Warburg effect') can significantly contribute to disease progression and chemoresistance and hence, it has been exploited as novel drug target. This review focuses on the molecular cues of aberrant glycolysis as drivers of chemo-resistance and aggressiveness of recurrent ovarian cancer. Furthermore, we discuss the status quo of small molecule inhibition of aerobic glycolysis and significance of metabolic coupling between cancer cells and tumor microenvironment as novel therapeutic interventions against this lethal pathology.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Efeito Warburg em Oncologia/efeitos dos fármacos , Animais , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/patologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Terapia de Alvo Molecular , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Indução de Remissão , Resultado do Tratamento , Hipóxia Tumoral , Microambiente Tumoral
13.
Biochim Biophys Acta Rev Cancer ; 1876(1): 188568, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34023419

RESUMO

Pyruvate is irreversibly decarboxylated to acetyl coenzyme A by mitochondrial pyruvate dehydrogenase complex (PDC). Decarboxylation of pyruvate is considered a crucial step in cell metabolism and energetics. The cancer cells prefer aerobic glycolysis rather than mitochondrial oxidation of pyruvate. This attribute of cancer cells allows them to sustain under indefinite proliferation and growth. Pyruvate dehydrogenase kinases (PDKs) play critical roles in many diseases because they regulate PDC activity. Recent findings suggest an altered metabolism of cancer cells is associated with impaired mitochondrial function due to PDC inhibition. PDKs inhibit the PDC activity via phosphorylation of the E1a subunit and subsequently cause a glycolytic shift. Thus, inhibition of PDK is an attractive strategy in anticancer therapy. This review highlights that PDC/PDK axis could be implicated in cancer's therapeutic management by developing potential small-molecule PDK inhibitors. In recent years, a dramatic increase in the targeting of the PDC/PDK axis for cancer treatment gained an attention from the scientific community. We further discuss breakthrough findings in the PDC-PDK axis. In addition, structural features, functional significance, mechanism of activation, involvement in various human pathologies, and expression of different forms of PDKs (PDK1-4) in different types of cancers are discussed in detail. We further emphasized the gene expression profiling of PDKs in cancer patients to prognosis and therapeutic manifestations. Additionally, inhibition of the PDK/PDC axis by small molecule inhibitors and natural compounds at different clinical evaluation stages has also been discussed comprehensively.


Assuntos
Antineoplásicos/uso terapêutico , Metabolismo Energético/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piruvato Desidrogenase Quinase de Transferência de Acetil/antagonistas & inibidores , Complexo Piruvato Desidrogenase/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Mitocôndrias/enzimologia , Mitocôndrias/genética , Mitocôndrias/patologia , Terapia de Alvo Molecular , Neoplasias/enzimologia , Neoplasias/genética , Neoplasias/patologia , Fosforilação , Piruvato Desidrogenase Quinase de Transferência de Acetil/genética , Piruvato Desidrogenase Quinase de Transferência de Acetil/metabolismo , Transdução de Sinais , Efeito Warburg em Oncologia/efeitos dos fármacos
14.
Mol Cell Biochem ; 476(9): 3423-3431, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33970409

RESUMO

Reprogramming of energy metabolism is a hallmark of cancer which is prevalent worldwide. Octamer transcription factor-1 (OCT1) is a well-known transcription factor. However, the role of OCT1 in metabolism remodeling has not been well defined. In the present study, we found that OCT1 was up-regulated in non-small cell lung cancer (NSCLC) and correlated with poor patient survival. Further data identified that OCT1 increased glycolysis flux, promoting proliferation in lung cancer cells. Mechanistically, OCT1 facilitated the aerobic glycolysis and cell proliferation via up-regulation of hexokinase 2 (HK2), a crucial enzyme of the Warburg effect. Hence, our findings indicate that, in NSCLC, high levels of OCT1 contribute to the Warburg effect through up-regulation of HK2, linking up the OCT1/HK2 axis and cancer progression, which provide a potential biomarker and therapeutic target for NSCLC treatment.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Regulação Neoplásica da Expressão Gênica , Hexoquinase/metabolismo , Neoplasias Pulmonares/patologia , Fator 1 de Transcrição de Octâmero/metabolismo , Efeito Warburg em Oncologia , Apoptose , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proliferação de Células , Glicólise , Hexoquinase/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Fator 1 de Transcrição de Octâmero/genética , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas
15.
Nat Commun ; 12(1): 2620, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976173

RESUMO

Tumor associated macrophage responses are regulated by distinct metabolic states that affect their function. However, the ability of specific signals in the local tumor microenvironment to program macrophage metabolism remains under investigation. Here, we identify NAMPT, the rate limiting enzyme in NAD salvage synthesis, as a target of STAT1 during cellular activation by interferon gamma, an important driver of macrophage polarization and antitumor responses. We demonstrate that STAT1 occupies a conserved element within the first intron of Nampt, termed Nampt-Regulatory Element-1 (NRE1). Through disruption of NRE1 or pharmacological inhibition, a subset of M1 genes is sensitive to NAMPT activity through its impact on glycolytic processes. scRNAseq is used to profile in vivo responses by NRE1-deficient, tumor-associated leukocytes in melanoma tumors through the creation of a unique mouse strain. Reduced Nampt and inflammatory gene expression are present in specific myeloid and APC populations; moreover, targeted ablation of NRE1 in macrophage lineages results in greater tumor burden. Finally, elevated NAMPT expression correlates with IFNγ responses and melanoma patient survival. This study identifies IFN and STAT1-inducible Nampt as an important factor that shapes the metabolic program and function of tumor associated macrophages.


Assuntos
Citocinas/genética , Melanoma/genética , Nicotinamida Fosforribosiltransferase/genética , Fator de Transcrição STAT1/metabolismo , Neoplasias Cutâneas/genética , Macrófagos Associados a Tumor/imunologia , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Elementos Facilitadores Genéticos , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Células HEK293 , Humanos , Interferon gama/metabolismo , Estimativa de Kaplan-Meier , Masculino , Melanoma/imunologia , Melanoma/mortalidade , Melanoma/patologia , Camundongos , Camundongos Knockout , Nicotinamida Fosforribosiltransferase/metabolismo , Células RAW 264.7 , RNA-Seq , Receptores de Interferon/genética , Receptores de Interferon/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Células THP-1 , Macrófagos Associados a Tumor/metabolismo , Regulação para Cima , Efeito Warburg em Oncologia
16.
Medicine (Baltimore) ; 100(18): e25545, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33950928

RESUMO

BACKGROUND: Breast cancer is a common malignant tumor in women. In recent years, its incidence is increasing year by year, and its morbidity and mortality rank the first place among female malignant tumors. Some key enzymes and intermediates in glycolysis are closely related to tumor development. Pyruvate kinase M2 (PKM2) is an important rate-limiting enzyme in glycolysis pathway. Meanwhile, it is highly expressed in proliferative cells, especially in tumor cells, and plays an important role in the formation of Warburg effect and tumorigenesis. Previous studies have explored the effects of PKM2 expression on the prognosis and clinical significance of breast cancer patients, while the results are contradictory and uncertain. This study uses controversial data for meta-analysis to accurately evaluate the problem. We collected relevant Oncomine and The Cancer Genome Atlas (TCGA) data to further verify the results. Through bioinformatics analysis, the mechanism and related pathways of PKM2 in breast cancer are explored. METHODS: We searched Wanfang, Chinese Biomedical Literature Database, Chinese National Knowledge Infrastructure, the Chongqing VIP Chinese Science and Technology Periodical Database, PubMed, Embase, and Web of Science databases from inception to March 2021. The language restrictions are Chinese and English. The published literatures on PKM2 expression and prognosis or clinicopathological characteristics of breast cancer patients were statistically analyzed. Combined hazard ratios (HRs), odds ratios (ORs), and 95% confidence intervals (95% CIs) were used to evaluate the effects of PKM2 on the prognosis and clinicopathological features of breast cancer. Stata 14.0 software was applied for meta-analysis. Oncomine and TCGA databases were used to meta-analyze the differences of PKM2 mRNA expression between breast cancer and normal breast tissues. The expression of PKM2 protein was verified by Human Protein Atlas (HPA) database. The relationship between the gene and the survival of breast cancer patients was analyzed by Gene Expression Profiling Interactive Analysis (GEPIA). The relationship between PKM2 gene and clinicopathological characteristics was analyzed by using LinkedOmics, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathway analysis was performed by using Metascape. Protein-protein interaction (PPI) network was constructed by String website. RESULTS: The results of this meta-analysis will be submitted to a peer-reviewed journal for publication. CONCLUSION: This study provides high-quality medical evidence for the correlation between the expression of PKM2 and the prognosis and clinicopathological features of breast cancer. Through bioinformatics analysis, this study further deepens the understanding of the mechanism and related pathways of PKM2 in breast cancer. ETHICS AND DISSEMINATION: The private information from individuals will not be published. This systematic review also should not damage participants' rights. Ethical approval is not available. The results may be published in a peer-reviewed journal or disseminated in relevant conferences. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/W52HB.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/mortalidade , Mama/patologia , Carcinogênese/patologia , Proteínas de Transporte/metabolismo , Proteínas de Membrana/metabolismo , Hormônios Tireóideos/metabolismo , Biomarcadores Tumorais/análise , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Proteínas de Transporte/análise , Biologia Computacional , Intervalo Livre de Doença , Feminino , Humanos , Proteínas de Membrana/análise , Metanálise como Assunto , Prognóstico , Medição de Risco/métodos , Hormônios Tireóideos/análise , Efeito Warburg em Oncologia
17.
Life Sci ; 278: 119597, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33974932

RESUMO

This brief review describes the association of the endogenous pineal melatonin rhythm with the metabolic flux of solid tumors, particularly breast cancer. It also summarizes new information on the potential mechanisms by which endogenously-produced or exogenously-administered melatonin impacts the metabolic phenotype of cancer cells. The evidence indicates that solid tumors may redirect their metabolic phenotype from the pathological Warburg-type metabolism during the day to the healthier mitochondrial oxidative phosphorylation on a nightly basis. Thus, they function as cancer cells only during the day and as healthier cells at night, that is, they are only part-time cancerous. This switch to oxidative phosphorylation at night causes cancer cells to exhibit a reduced tumor phenotype and less likely to rapidly proliferate or to become invasive or metastatic. Also discussed is the likelihood that some solid tumors are especially aggressive during the day and much less so at night due to the nocturnal rise in melatonin which determines their metabolic state. We further propose that when melatonin is used/tested in clinical trials, a specific treatment paradigm be used that is consistent with the temporal metabolic changes in tumor metabolism. Finally, it seems likely that the concurrent use of melatonin in combination with conventional chemotherapies also would improve cancer treatment outcomes.


Assuntos
Melatonina/metabolismo , Neoplasias/metabolismo , Efeito Warburg em Oncologia , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Humanos , Melatonina/farmacologia , Melatonina/uso terapêutico , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Fosforilação Oxidativa/efeitos dos fármacos , Efeito Warburg em Oncologia/efeitos dos fármacos
18.
Biochem Pharmacol ; 188: 114537, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33811907

RESUMO

Mitochondria are a major source of ATP provision as well as cellular suicidal weapon store. Accumulating evidences demonstrate that mitochondrial bioenergetics, biosynthesis and signaling are important mediators of tumorigenesis. Metabolic plasticity enables cancer cell reprogramming to cope with cellular and environmental alterations, a process requires mitochondria biology. Mitochondrial metabolism emerges to be a promising arena for cancer therapeutic targets. The permeability transition pore (PTP) participates in physiological Ca2+ and ROS homeostasis as well as cell death depending on the open state. The hypothesis that PTP forms from F-ATP synthase provides clues to the potential collaborative role of mitochondrial respiration and PTP in regulating cancer cell fate and metabolic reprogramming.


Assuntos
Reprogramação Celular/fisiologia , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Poro de Transição de Permeabilidade Mitocondrial/metabolismo , Neoplasias/metabolismo , Efeito Warburg em Oncologia , Animais , Metabolismo Energético/fisiologia , Glicólise/fisiologia , Humanos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/genética , Neoplasias/genética , Permeabilidade
19.
Biomolecules ; 11(5)2021 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-33925206

RESUMO

The Warburg effect has been considered a potential therapeutic target to fight against cancer progression. In KRAS mutant cells, PKM2 (pyruvate kinase isozyme M2) is hyper-activated, and it induces GLUT1 expression; therefore, KRAS has been closely involved in the initiation of Warburg metabolism. Although mTOR (mammalian target of rapamycin), a well-known inhibitor of autophagy-dependent survival in physiological conditions, is also activated in KRAS mutants, many recent studies have revealed that autophagy becomes hyper-active in KRAS mutant cancer cells. In the present study, a mathematical model was built containing the main elements of the regulatory network in KRAS mutant cancer cells to explore the further possible therapeutic strategies. Our dynamical analysis suggests that the downregulation of KRAS, mTOR and autophagy are crucial in anti-cancer therapy. PKM2 has been assumed to be the key switch in the stress response mechanism. We predicted that the addition of both pharmacologic ascorbate and chloroquine is able to block both KRAS and mTOR pathways: in this case, no GLUT1 expression is observed, meanwhile autophagy, essential for KRAS mutant cancer cells, is blocked. Corresponding to our system biological analysis, this combined pharmacologic ascorbate and chloroquine treatment in KRAS mutant cancers might be a therapeutic approach in anti-cancer therapies.


Assuntos
Cloroquina/farmacologia , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Modelos Teóricos , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Piruvato Quinase/efeitos dos fármacos , Piruvato Quinase/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Efeito Warburg em Oncologia/efeitos dos fármacos
20.
Biochim Biophys Acta Rev Cancer ; 1876(1): 188553, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33915221

RESUMO

The commencement of cancer is attributed to one or a few cells that become rogue and attain the property of immortality. The inception of distinct cancer cell clones during the hyperplastic and dysplastic stages of cancer progression is the utimate consequence of the dysregulated cellular pathways and the proliferative potential itself. Furthermore, a critical factor that adds a layer of complexity to this pre-existent intra-tumoral heterogeneity (ITH) is the foundation of an oxygen gradient, that is established due to the improper architecture of the tumor vasculature. Therefore, as a resultant effect, the poorly oxygenated regions thus formed and characterized as hypoxic, promote the emergence of aggressive and treatment-resistant cancer cell clones. The extraordinary property of the hypoxic cancer cells to exist harmoniously with cancerous and non-cancerous cells in the tumor microenvironment (TME) further increases the intricacies of ITH. Here in this review, the pivotal influence of differential oxygen concentrations in shaping the ITH is thoroughly discussed. We also emphasize on the vitality of the interacting networks that govern the overall fate of oxygen gradient-dependent origin of tumor heterogeneity. Additionally, the implications of less-appreciated reverse Warburg effect, a symbiotic metabolic coupling, and the associated epigenetic regulation of rewiring of cancer metabolism in response to oxygen gradients, have been highlighted as critical influencers of ITH.


Assuntos
Heterogeneidade Genética , Neoplasias/metabolismo , Oxigênio/metabolismo , Microambiente Tumoral , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Comunicação Celular , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Humanos , Fator 1 Induzível por Hipóxia/genética , Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias/genética , Neoplasias/patologia , Transdução de Sinais , Hipóxia Tumoral , Efeito Warburg em Oncologia
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