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1.
Theranostics ; 12(14): 6395-6408, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36168616

RESUMO

Rationale: The overall clinical response to FGFR inhibitor (FGFRi) is far from satisfactory in cancer patients stratified by FGFR aberration, the current biomarker in clinical practice. A novel biomarker to evaluate the therapeutic response to FGFRi in a non-invasive and dynamic manner is thus greatly desired. Methods: Six FGFR-aberrant cancer cell lines were used, including four FGFRi-sensitive ones (NCI-H1581, NCI-H716, RT112 and Hep3B) and two FGFRi-resistant ones (primary for NCI-H2444 and acquired for NCI-H1581/AR). Cell viability and tumor xenograft growth analyses were performed to evaluate FGFRi sensitivities, accompanied by corresponding 18F-fluorodeoxyglucose (18F-FDG) uptake assay. mTOR/PLCγ/MEK-ERK signaling blockade by specific inhibitors or siRNAs was applied to determine the regulation mechanism. Results: FGFR inhibition decreased the in vitro accumulation of 18F-FDG only in four FGFRi-sensitive cell lines, but in neither of FGFRi-resistant ones. We then demonstrated that FGFRi-induced transcriptional downregulation of hexokinase 2 (HK2), a key factor of glucose metabolism and FDG trapping, via mTOR pathway leading to this decrease. Moreover, 18F-FDG PET imaging successfully differentiated the FGFRi-sensitive tumor xenografts from primary or acquired resistant ones by the tumor 18F-FDG accumulation change upon FGFRi treatment. Of note, both 18F-FDG tumor accumulation and HK2 expression could respond the administration/withdrawal of FGFRi in NCI-H1581 xenografts correspondingly. Conclusion: The novel association between the molecular mechanism (FGFR/mTOR/HK2 axis) and radiological phenotype (18F-FDG PET uptake) of FGFR-targeted therapy was demonstrated in multiple preclinical models. The adoption of 18F-FDG PET biomarker-based imaging strategy to assess response/resistance to FGFR inhibition may benefit treatment selection for cancer patients.


Assuntos
Fluordesoxiglucose F18 , Neoplasias , Biomarcadores , Linhagem Celular Tumoral , Fluordesoxiglucose F18/metabolismo , Glucose/metabolismo , Hexoquinase , Humanos , Quinases de Proteína Quinase Ativadas por Mitógeno , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Tomografia por Emissão de Pósitrons , Inibidores de Proteínas Quinases/farmacologia , Serina-Treonina Quinases TOR
2.
Int J Mol Sci ; 23(17)2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36077431

RESUMO

Aerobic glycolysis is an emerging hallmark of many human cancers, as cancer cells are defined as a "metabolically abnormal system". Carbohydrates are metabolically reprogrammed by its metabolizing and catabolizing enzymes in such abnormal cancer cells. Normal cells acquire their energy from oxidative phosphorylation, while cancer cells acquire their energy from oxidative glycolysis, known as the "Warburg effect". Energy-metabolic differences are easily found in the growth, invasion, immune escape and anti-tumor drug resistance of cancer cells. The glycolysis pathway is carried out in multiple enzymatic steps and yields two pyruvate molecules from one glucose (Glc) molecule by orchestral reaction of enzymes. Uncontrolled glycolysis or abnormally activated glycolysis is easily observed in the metabolism of cancer cells with enhanced levels of glycolytic proteins and enzymatic activities. In the "Warburg effect", tumor cells utilize energy supplied from lactic acid-based fermentative glycolysis operated by glycolysis-specific enzymes of hexokinase (HK), keto-HK-A, Glc-6-phosphate isomerase, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase, phosphofructokinase (PFK), phosphor-Glc isomerase (PGI), fructose-bisphosphate aldolase, phosphoglycerate (PG) kinase (PGK)1, triose phosphate isomerase, PG mutase (PGAM), glyceraldehyde-3-phosphate dehydrogenase, enolase, pyruvate kinase isozyme type M2 (PKM2), pyruvate dehydrogenase (PDH), PDH kinase and lactate dehydrogenase. They are related to glycolytic flux. The key enzymes involved in glycolysis are directly linked to oncogenesis and drug resistance. Among the metabolic enzymes, PKM2, PGK1, HK, keto-HK-A and nucleoside diphosphate kinase also have protein kinase activities. Because glycolysis-generated energy is not enough, the cancer cell-favored glycolysis to produce low ATP level seems to be non-efficient for cancer growth and self-protection. Thus, the Warburg effect is still an attractive phenomenon to understand the metabolic glycolysis favored in cancer. If the basic properties of the Warburg effect, including genetic mutations and signaling shifts are considered, anti-cancer therapeutic targets can be raised. Specific therapeutics targeting metabolic enzymes in aerobic glycolysis and hypoxic microenvironments have been developed to kill tumor cells. The present review deals with the tumor-specific Warburg effect with the revisited viewpoint of recent progress.


Assuntos
Glicólise , Neoplasias , Hexoquinase/metabolismo , Humanos , Neoplasias/metabolismo , Fosfofrutoquinase-1/metabolismo , Fosfoglicerato Quinase/metabolismo , Fosfoglicerato Mutase/metabolismo , Piruvatos , Microambiente Tumoral
3.
Cells ; 11(18)2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-36139434

RESUMO

In pediatric rhabdomyosarcoma (RMS), elevated Akt signaling is associated with increased malignancy. Here, we report that expression of a constitutively active, myristoylated form of Akt1 (myrAkt1) in human RMS RD cells led to hyperactivation of the mammalian target of rapamycin (mTOR)/70-kDa ribosomal protein S6 kinase (p70S6K) pathway, resulting in the loss of both MyoD and myogenic capacity, and an increase of Ki67 expression due to high cell mitosis. MyrAkt1 signaling increased migratory and invasive cell traits, as detected by wound healing, zymography, and xenograft zebrafish assays, and promoted repair of DNA damage after radiotherapy and doxorubicin treatments, as revealed by nuclear detection of phosphorylated H2A histone family member X (γH2AX) through activation of DNA-dependent protein kinase (DNA-PK). Treatment with synthetic inhibitors of phosphatidylinositol-3-kinase (PI3K) and Akt was sufficient to completely revert the aggressive cell phenotype, while the mTOR inhibitor rapamycin failed to block cell dissemination. Furthermore, we found that pronounced Akt1 signaling increased the susceptibility to cell apoptosis after treatments with 2-deoxy-D-glucose (2-DG) and lovastatin, enzymatic inhibitors of hexokinase, and 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), especially in combination with radiotherapy and doxorubicin. In conclusion, these data suggest that restriction of glucose metabolism and the mevalonate pathway, in combination with standard therapy, may increase therapy success in RMS tumors characterized by a dysregulated Akt signaling.


Assuntos
Proteínas Proto-Oncogênicas c-akt , Rabdomiossarcoma Embrionário , Animais , Criança , DNA/metabolismo , Reparo do DNA , Proteína Quinase Ativada por DNA/genética , Desoxiglucose , Doxorrubicina/farmacologia , Glucose , Glicólise , Hexoquinase/metabolismo , Histonas/metabolismo , Humanos , Antígeno Ki-67/metabolismo , Lovastatina , Inibidores MTOR , Mamíferos/metabolismo , Ácido Mevalônico , Oxirredutases/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositóis , Proteínas Proto-Oncogênicas c-akt/metabolismo , Rabdomiossarcoma Embrionário/tratamento farmacológico , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Peixe-Zebra/genética
4.
Arch Biochem Biophys ; 729: 109389, 2022 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-36075458

RESUMO

BACKGROUND: Cervical cancer is one of the most common cancers in women worldwide. Hexokinase 2 (HK2) is responsible for phosphorylating glucose into glucose-6-phosphate, which is required for tumorigenesis and metastasis. METHODS: E6E7 and FTO were exogenously expressed, and their effects on HK2 mRNA and protein levels were detected by RT-qPCR and Western blot. RESULTS: The exogenous expression of E6E7 in SiHa and C33A cells up-regulated the mRNA and protein levels of intracellular HK2, up-regulated the total m6A levels, changed the expression of m6A proteins and activated the GSK3ß transcription. The expression levels of METTL3 and WTAP were enhanced, whereas the expression of FTO and ALKBH5 were decreased. In addition, FTO down-regulated the mRNA and protein levels of HK2. FTO overexpression partially inhibited the up-regulated expression of HK2 caused by E6E7. Furthermore, FTO overexpression increased the level of HK2 pre-mRNA in the nucleus and decreased the level of mature HK2 mRNA in the cytoplasm. We also found that GSK3ß overexpression enhanced FTO ubiquitination and decreased FTO protein levels. CONCLUSION: This study found that E6E7 oncogene activates the transcription of GSK3ß; GSK3ß can promote the ubiquitination-proteasomal degradation of FTO and reduce the level of FTO protein; FTO inhibits the maturation and translation of HK2 mRNA by retaining HK2 pre-mRNA in the nucleus.


Assuntos
Hexoquinase , Neoplasias do Colo do Útero , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Feminino , Glucose , Glucose-6-Fosfato , Glicogênio Sintase Quinase 3 beta/genética , Hexoquinase/genética , Humanos , Metiltransferases/metabolismo , Precursores de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia
5.
Cancer Biol Med ; 19(9)2022 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-36172793

RESUMO

OBJECTIVE: Osteosarcoma (OS) is an aggressive, highly metastatic, relatively drug-resistant bone tumor with poor long-term survival rates. The presence and persistence of circulating tumor cells (CTCs) in the peripheral blood are believed to be associated with treatment inefficiency and distant metastases. A blood-based CTC test is thus greatly needed for monitoring disease progression and predicting clinical outcomes. However, traditional methods cannot detect CTCs from tumors of mesenchymal origin such as OS, and research on CTC detection in mesenchymal tumors has been hindered for years. METHODS: In this study, we developed a CTC test based on hexokinase 2, a metabolic function-associated marker, for the detection and surveillance of OS CTCs, and subsequently explored its clinical value. Twelve patients with OS were enrolled as the training cohort for serial CTC tests. Dynamic CTC counting, in combination with therapy evaluation and post-treatment follow-up, was used to establish a model for predicting post-chemotherapy evaluation and disease-free survival, and the model was further validated with a cohort of 8 patients with OS. RESULTS: Two dynamic CTC number patterns were identified, and the resulting predictive model exhibited 92% consistency with the clinical outcomes. This model suggested that a single CTC test has similar predictive power to serial CTC analysis. In the validation cohort, the single CTC test exhibited 100% and 87.5% consistency with therapy response and disease-free survival, respectively. CONCLUSIONS: Our non-invasive test for detection and surveillance of CTCs enables accurate prediction of therapy efficiency and prognosis, and may be clinically valuable for avoiding inefficient therapy and prolonging survival.


Assuntos
Neoplasias Ósseas , Células Neoplásicas Circulantes , Osteossarcoma , Biomarcadores Tumorais , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/tratamento farmacológico , Hexoquinase , Humanos , Células Neoplásicas Circulantes/patologia , Osteossarcoma/tratamento farmacológico , Prognóstico
6.
BMC Cancer ; 22(1): 900, 2022 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-35982398

RESUMO

BACKGROUND: Hexokinase 2 (HK2) is an enzyme that catalyses the conversion of glucose to glucose-6-phosphate, which has been found to be associated with malignant tumour growth. However, the potential immunological and clinical significance of HK2, especially in terms of prognostic prediction for patients with glioma, has not been fully elucidated. METHODS: To investigate the expression, immunological and clinical significance of HK2 in patients with glioma, several databases, including ONCOMINE, TIMER2.0, GEPIA, CGGA, UCSC, LinkedOmics, Metascape, STRING, GSCA, and TISIDB, as well as biochemical, cellular, and pathological analyses, were used in this study. In addition, we performed univariate, multivariate Cox regression and nomogram analyses of the hub genes positively and negatively correlated with HK2 to explore the potential regulatory mechanism in the initiation and development of glioma. RESULTS: Our results demonstrated that HK2 was highly expressed in most malignant cancers. HK2 expression was significantly higher in lower grade glioma (LGG) and glioblastoma (GBM) than in adjacent normal tissue. In addition, HK2 expression was significantly correlated with clinical parameters, histological manifestations, and prognosis in glioma patients. Specifically, the data from The Cancer Genome Atlas downloaded from UCSC Xena database analysis showed that high expression of HK2 was strongly associated with poor prognosis in glioma patients. The LinkedOmics database indicated that HK2-related genes were mainly enriched in immune-related cells. In LGG and GBM tissues, HK2 expression is usually correlated with recognized immune checkpoints and the abundance of multiple immune infiltrates. Similarly, the Metascape database revealed that HK2-related genes were mainly enriched and annotated in immune-related pathways and immune cells. Further investigations also confirmed that the inhibition of HK2 expression remarkably suppressed metastasis and vasculogenic mimicry (VM) formation in glioma cells through regulating the gene expression of inflammatory and immune modulators. CONCLUSION: HK2 expression was closely associated with the malignant properties of glioma through activating multiple immune-related signalling pathways to regulate immune responses and the infiltration of immune cells. Thus, HK2 and its hub genes may be a potential target for the treatment of glioma.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioma , Hexoquinase/metabolismo , Neoplasias Encefálicas/patologia , Glioma/patologia , Hexoquinase/genética , Humanos , Prognóstico
7.
J Med Chem ; 65(17): 11633-11647, 2022 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-35984330

RESUMO

The voltage-dependent anion channel (VDAC), the most abundant protein on the outer mitochondrial membrane, is implicated in ATP, ion and metabolite exchange with cell compartments. In particular, the VDAC participates in cytoplasmic and mitochondrial Ca2+ homeostasis. Notably, the Ca2+ efflux out of Schwann cell mitochondria is involved in peripheral nerve demyelination that underlies most peripheral neuropathies. Hexokinase (HK) isoforms I and II, the main ligands of the VDAC, possess a hydrophobic N-terminal structured in α-helix (NHKI) that is necessary for the binding to the VDAC. To gain further insight into the molecular basis of HK binding to the VDAC, we developed and optimized peptides based on the NHKI sequence. These modifications lead to an increase of the peptide hydrophobicity and helical content that enhanced their ability to prevent peripheral nerve demyelination. Our results provide new insights into the molecular basis of VDAC/HK interaction that could lead to the development of therapeutic compounds for demyelinating peripheral neuropathies.


Assuntos
Doenças Desmielinizantes , Doenças do Sistema Nervoso Periférico , Sítios de Ligação , Hexoquinase , Humanos , Nervos Periféricos/metabolismo , Canais de Ânion Dependentes de Voltagem/metabolismo
8.
Food Chem ; 397: 133739, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-35940100

RESUMO

This study examined cooperative regulation of phosphorylation and acetylation of glycolytic enzymes on their activity and lamb meat quality. Muscle samples were divided into two groups (fast and slow) according to their glycolysis rate as defined by pH decline rate from 1 h to 1 d postmortem. In slow glycolysis rate group, the activity of hexokinase (HK), phosphofructokinase (PFK) and pyruvate kinase (PK) was lower and meat sample showed lower a*, higher shear force and cooking loss. The acetylation and phosphorylation of HK were positively correlated with HK activity. The acetylation and phosphorylation of PFK were correlated with shear force and negatively associated with PFK activity. The acetylation and phosphorylation of PK were significantly correlated with each other but showed insignificant correlations with PK activity. Briefly, the phosphorylation and acetylation of HK, PFK and PK coregulate glycolysis through different crosstalk patterns on their activity and this might affect meat quality.


Assuntos
Fosfofrutoquinase-1 , Carne Vermelha , Acetilação , Animais , Glicólise , Hexoquinase/genética , Hexoquinase/metabolismo , Fosfofrutoquinase-1/metabolismo , Fosfofrutoquinases , Fosforilação , Piruvato Quinase/genética , Piruvato Quinase/metabolismo , Ovinos
9.
Cell Commun Signal ; 20(1): 132, 2022 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-36042519

RESUMO

Osteoarthritis (OA) is an age-related chronic degenerative joint disease where the main characteristics include progressive degeneration of cartilage, varying degrees of synovitis, and periarticular osteogenesis. However, the underlying factors involved in OA pathogenesis remain elusive which has resulted in poor clinical treatment effect. Recently, glucose metabolism changes provide a new perspective on the pathogenesis of OA. Under the stimulation of external environment, the metabolic pathway of chondrocytes tends to change from oxidative phosphorylation (OXPHOS) to aerobic glycolysis. Previous studies have demonstrated that glycolysis of synovial tissue is increased in OA. The hexokinase (HK) is the first rate limiting enzyme in aerobic glycolysis, participating and catalyzing the main pathway of glucose utilization. An isoform of HKs, HK2 is considered to be a key regulator of glucose metabolism, promotes the transformation of glycolysis from OXPHOS to aerobic glycolysis. Moreover, the expression level of HK2 in OA synovial tissue (FLS) was higher than that in control group, which indicated the potential therapeutic effect of HK2 in OA. However, there is no summary to help us understand the potential therapeutic role of glucose metabolism in OA. Therefore, this review focuses on the properties of HK2 and existing research concerning HK2 and OA. We also highlight the potential role and mechanism of HK2 in OA. Video abstract.


Assuntos
Glicólise , Hexoquinase/metabolismo , Osteoartrite , Glucose/metabolismo , Humanos , Osteoartrite/metabolismo , Membrana Sinovial/patologia
10.
Theor Appl Genet ; 135(10): 3417-3431, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35941236

RESUMO

KEY MESSAGE: We report the map-based cloning and functional characterization of SNG1, which encodes OsHXK3, a hexokinase-like protein that plays a pivotal role in controlling grain size in rice. Grain size is an important agronomic trait determining grain yield and appearance quality in rice. Here, we report the discovery of rice mutant short and narrow grain1 (sng1) with reduced grain length, width and weight. Map-based cloning revealed that the mutant phenotype was caused by loss of function of gene OsHXK3 that encodes a hexokinase-like (HKL) protein. OsHXK3 was associated with the mitochondria and was ubiquitously distributed in various organs, predominately in younger organs. Analysis of glucose (Glc) phosphorylation activities in young panicles and protoplasts showed that OsHXK3 was a non-catalytic hexokinase (HXK). Overexpression of OsHXK3 could not complement the Arabidopsis glucose insensitive2-1 (gin2-1) mutant, indicating that OsHXK3 lacked Glc signaling activity. Scanning electron microscopy analysis revealed that OsHXK3 affects grain size by promoting spikelet husk cell expansion. Knockout of other nine OsHXK genes except OsHXK3 individually did not change grain size, indicating that functions of OsHXKs have differentiated in rice. OsHXK3 influences gibberellin (GA) biosynthesis and homeostasis. Compared with wild type, OsGA3ox2 was significantly up-regulated and OsGA2ox1 was significantly down-regulated in young panicle of sng1, and concentrations of biologically active GAs were significantly decreased in young panicles of the mutants. The yield per plant of OsHXK3 overexpression lines (OE-4 and OE-35) was increased by 10.91% and 7.62%, respectively, compared to that of wild type. Our results provide evidence that an HXK lacking catalytic and sensory functions plays an important role in grain size and has the potential to increase yield in rice.


Assuntos
Oryza , Grão Comestível/genética , Grão Comestível/metabolismo , Regulação da Expressão Gênica de Plantas , Giberelinas/metabolismo , Glucose/metabolismo , Hexoquinase/genética , Hexoquinase/metabolismo , Oryza/genética , Oryza/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo
11.
Eur J Pharmacol ; 931: 175226, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36007607

RESUMO

Metastasis is the leading cause of death in melanoma patients. Aerobic glycolysis is a common metabolic feature in tumor and is closely related to cell growth and metastasis. Kaempferol (KAM) is one of the active ingredients in the total flavonoids of Chinese traditional medicine Sparganii Rhizoma. Studies have shown that it interferes with the cell cycle, apoptosis, angiogenesis and metastasis of tumor cells, but whether it can affect the aerobic glycolysis of melanoma is still unclear. Here, we explored the effects and mechanisms of KAM on melanoma metastasis and aerobic glycolysis. KAM inhibited the migration and invasion of A375 and B16F10 cells, and reduced the lung metastasis of melanoma cells. Extracellular acidification rates (ECAR) and glucose consumption were obviously suppressed by KAM, as well as the production of ATP, pyruvate and lactate. Mechanistically, the activity of hexokinase (HK), the first key kinase of aerobic glycolysis, was significantly inhibited by KAM. Although the total protein expression of HK2 was not significantly changed, the binding of HK2 and voltage-dependent anion channel 1 (VDAC1) on mitochondria was inhibited by KAM through AKT/GSK-3ß signal pathway. In conclusion, KAM inhibits melanoma metastasis via blocking aerobic glycolysis of melanoma cells, in which the binding of HK2 and VDAC1 on mitochondria was broken.


Assuntos
Melanoma , Canal de Ânion 1 Dependente de Voltagem , Linhagem Celular Tumoral , Proliferação de Células , Glicogênio Sintase Quinase 3 beta/metabolismo , Glicólise , Hexoquinase/metabolismo , Humanos , Quempferóis/farmacologia , Melanoma/patologia , Mitocôndrias/metabolismo , Canal de Ânion 1 Dependente de Voltagem/metabolismo
12.
J Ovarian Res ; 15(1): 92, 2022 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-35953860

RESUMO

BACKGROUND: Recently, increasing evidence has indicated that elevation of Hexokinase 2 (HK2) plays an important role in several cancers on regulating cell motility and growth. However, its role on regulating cell EMT in human ovarian cancer still less to known. METHODS: The transwell and wound-healing assay were used to detect the effective of HK2 on regulating motility of ovarian cancer cells. Real Time PCR and Western Blotting were used to explore the changing of EMT-related proteins in HK2-modified cells. The clonogenic formation, cell growth curves and MTT assays were used to evaluate the effective of HK2 on regulating cell proliferation in HK2-modified cells. The flow cytometry was used to detect the differences in the distribution of cells in the cell cycle between the HK2-modified cells and their control cells. The correlation of HK2 and Akt1/p-Akt1 was explored by using Western Blotting, Akt1 inhibitor (MK2206) and transient transfection of an Akt1 recombinant plasmid. The potential correlation between HK2 and EMT-related proteins in human ovarian cancer tissues and OV (ovarian serous cystadenocarcinoma) was confirmed by using Pearson correlation analysis and TIMER 2.0. RESULTS: In ovarian cancer cells, overexpressing of HK2 enhanced cell motility by inducing of EMT-related proteins, such as CDH2, fibronectin, MMP9, ZEB1, ZEB2 and vimentin. Moreover, overexpressing of HK2 promoted cell growth by reducing p21 and p27 expression in ovarian cancer cells. Further studies demonstrated that this promotion of cell motility and growth by HK2 was probably a result of it activating of Akt1 (p-Akt1) in ovarian cancer cells. Additionally, the positive correlation between HK2 and p-Akt1, fibronectin, MMP9 expression in human ovarian cancer samples was verified by using Pearson correlation analysis. The positive correlation between HK2 and CDH2, fibronectin, MMP9, ZEB1, ZEB2 and vimentin in OV (ovarian serous cystadenocarcinoma) was confirmed by using TIMER 2.0. CONCLUSION: This study demonstrated that HK2 could induce EMT-related proteins and reduce cell cycle inhibitor by activating Akt1 in human ovarian cancer cells, subsequently enhancing cell motility and growth, suggesting that HK2 participate in the malignant process of ovarian cancer by interacting with Akt1.


Assuntos
Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Carcinoma Epitelial do Ovário , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Fibronectinas/metabolismo , Hexoquinase/análise , Hexoquinase/genética , Humanos , Metaloproteinase 9 da Matriz , Neoplasias Ovarianas/patologia , Proteínas Proto-Oncogênicas c-akt , Vimentina/metabolismo
13.
Biomed Environ Sci ; 35(7): 622-632, 2022 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-35945177

RESUMO

Objective: To investigate the regulatory relationship of Protein Phosphatase 2 Regulatory Subunit B"Alpha ( PPP2R3A) and hexokinase 1 ( HK1) in glycolysis of hepatocellular carcinoma (HCC). Methods: In HepG2 and Huh7 cells, PPP2R3A expression was silenced by small interfering RNA (siRNA) and overexpression by plasmid transfection. The PPP2R3A-related genes were searched by RNA sequencing. Glycolysis levels were measured by glucose uptake and lactate production. QRT-PCR, ELISA, western blot and immunofluorescence assay were performed to detect the changes of PPP2R3A and HK1. Cell proliferation, migration and invasion assay were used to study the roles of HK1 regulation by PPP2R3A. Results: RNA sequencing data revealed that PPP2R3A siRNA significantly downregulated the expression of HK1. PPP2R3A gene overexpression promotes, while gene silencing suppresses, the level of HK1 and glycolysis in HCC cells. In HCC tissue samples, PPP2R3A and HK1 were colocalized in the cytoplasm, and their expression showed a positive correlation. HK1 inhibition abrogated the promotion of glycolysis, proliferation, migration and invasion by PPP2R3A overexpression in liver cancer cells. Conclusion: Our findings showed the correlation of PPP2R3A and HK1 in the glycolysis of HCC, which reveals a new mechanism for the oncogenic roles of PPP2R3A in cancer.


Assuntos
Carcinoma Hepatocelular , Hexoquinase/metabolismo , Neoplasias Hepáticas , Proteína Fosfatase 2/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Glicólise , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Proteína Fosfatase 2/genética , RNA Interferente Pequeno/metabolismo
14.
J Clin Lab Anal ; 36(9): e24641, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35949038

RESUMO

BACKGROUND: Circular RNAs (circRNAs) have been confirmed to be key regulators for colorectal cancer (CRC) progression. The purpose of this research was to explore the biological role and mechanism of hsa_circ_0045932 in CRC. METHODS: RT-qPCR and Western blot (WB) were applied to examine RNA and protein levels, respectively. MTT assay, EdU assay, and transwell assay were used to detect cell proliferative, migration, and invasion. Glucose uptake and lactic acid level were determined to assess cellular glycolysis. Dual-luciferase reporter and RIP assays were carried out to detect the relationship between miR-873-5p and hsa_circ_0045932 or hexokinase 2 (HK2). Xenograft mice model was established to confirm the function of hsa_circ_0045932 in vivo. RESULTS: Hsa_circ_0045932 was overexpressed in CRC tissue samples and cells. Hsa_circ_0045932 knockdown repressed CRC cell proliferation, invasion, migration, and glycolysis abilities in vitro. MiR-873-5p could be sponged by hsa_circ_0045932, and its inhibitor also reversed the inhibitory effect of hsa_circ_0045932 knockdown on CRC cell progression. HK2 was targeted by miR-873-5p, and hsa_circ_0045932 regulated HK2 expression through targeting miR-873-5p. Overexpression of HK2 reversed the repressive effect of hsa_circ_0045932 knockdown on CRC cell malignant behaviors. Furthermore, the pro-tumor role of hsa_circ_0045932 in vivo was also confirmed using animal experiments. CONCLUSION: Hsa_circ_0045932 promoted CRC progression through sponging miR-873-5p to up-regulate HK2, which might offer novel therapeutic target for CRC clinical intervention.


Assuntos
Neoplasias Colorretais , MicroRNAs , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Hexoquinase/genética , Humanos , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética
15.
Eur J Pharmacol ; 932: 175208, 2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-35981603

RESUMO

Non-small cell lung cancer (NSCLC) has the highest incidence and mortality in the world. Aspirin has been reported to promote apoptosis, inhibit proliferation, stemness, angiogenesis, cancer-associated inflammation and migration in NSCLC. But the effect of aspirin on aerobic glycolysis in NSCLC is less reported. In the present study, we investigated whether aspirin blocked aerobic glycolysis of NSCLC cells to inhibit proliferation. Our results showed that aspirin inhibited viability, PCNA expression, ability of colony formation, dimished extracellular acidification rate (ECAR), oxygen consumption rate (OCR) and production of pyruvic acid and lactic acid, accompanied with reduced mitochondrial membrane potential (MMP), PGC-1α expression and ROS production, indicating mitochondrial dysfunction in NSCLC cells. AMPK and mitochondrial-localized deacetylase sirtuin 3 (SIRT3) were identified as the relevant molecular targets in glycolysis, but mechanism and relationship between AMPK and SIRT3 for aspirin induced glycolysis inhibition remain unknown in cancer cells. The investigation of underlying mechanism indicated that aspirin activated AMPK pathway to inhibit aerobic glycolysis and proliferation by upregulating SIRT3 after application of compound C (CC), an inhibitor of AMPK activity or SIRT3 siRNA. Upon activation of SIRT3, aspirin promoted the release of hexokinase-II (HK-II) from mitochondrial outer membrane to cytosol by deacetylating cyclophilin D (CypD). Consistently, aspirin significantly inhibited the growth of NSCLC xenografts and exhibited antitumor activity probably through AMPK/SIRT3/HK-II pathway in vivo. Collectively, AMPK/SIRT3/HK-II pathway plays a critical role in anticancer effects of aspirin, and our findings might serve as potential target for clinical practice and chemoprevention of aspirin in NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Sirtuína 3 , Proteínas Quinases Ativadas por AMP/metabolismo , Aspirina/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Proliferação de Células , Ciclofilina D , Glicólise , Hexoquinase/metabolismo , Humanos , Ácido Láctico , Neoplasias Pulmonares/tratamento farmacológico , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ácido Pirúvico , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 3/metabolismo
16.
J Mol Med (Berl) ; 100(10): 1441-1453, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35943566

RESUMO

Chronic stress has the potential to impair health and may increase the vulnerability for psychiatric disorders. Emerging evidence suggests that specific neurometabolic dysfunctions play a role herein. In mice, chronic social defeat (CSD) stress reduces cerebral glucose uptake despite hyperglycemia. We hypothesized that this metabolic decoupling would be reflected by changes in contact sites between mitochondria and the endoplasmic reticulum, important intracellular nutrient sensors, and signaling hubs. We thus analyzed the proteome of their biochemical counterparts, mitochondria-associated membranes (MAMs) from whole brain tissue obtained from CSD and control mice. This revealed a lack of the glucose-metabolizing enzyme hexokinase 3 (HK3) in MAMs from CSD mice. In controls, HK3 protein abundance in MAMs and also in striatal synaptosomes correlated positively with peripheral blood glucose levels, but this connection was lost in CSD. We conclude that the ability of HK3 to traffic to sites of need, such as MAMs or synapses, is abolished upon CSD and surmise that this contributes to a cellular dysfunction instigated by chronic stress. KEY MESSAGES : Chronic social defeat (CSD) alters brain glucose metabolism CSD depletes hexokinase 3 (HK3) from mitochondria-associated membranes (MAMs) CSD results in loss of positive correlation between blood glucose and HK3 in MAMs and synaptosomes.


Assuntos
Glicemia , Hexoquinase , Animais , Glicemia/metabolismo , Encéfalo/metabolismo , Glucose/metabolismo , Hexoquinase/metabolismo , Humanos , Camundongos , Membranas Mitocondriais/metabolismo
17.
Trends Endocrinol Metab ; 33(10): 665-667, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35953432

RESUMO

Hexokinase (HK)-1 mitochondrial-binding mechanisms and consequential physiological relevance remain unclear. Recently, De Jesus et al. studied myeloid cells with HK1 carrying mutated mitochondrial-binding domains (MBDs) and provided evidence that HK1 localization controls glucose metabolic fate. Increases in cytosolic HK1 may also contribute to the inflammation associated with diabetes and aging.


Assuntos
Hexoquinase , Mitocôndrias , Metabolismo dos Carboidratos , Glucose/metabolismo , Hexoquinase/genética , Hexoquinase/metabolismo , Humanos , Inflamação/metabolismo , Mitocôndrias/metabolismo
18.
FEMS Yeast Res ; 21(1)2022 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-35918180

RESUMO

Sugar transporter research focuses on the sugar uptake into cells. Under certain physiological conditions, however, the intracellular accumulation and secretion of carbohydrates (efflux) are relevant processes in many cell types. Currently, no cell-based system is available for specifically investigating glucose efflux. Therefore, we designed a system based on a hexose transporter-deficient Saccharomyces cerevisiae strain, in which the disaccharide maltose is provided as a donor of intracellular glucose. By deleting the hexokinase genes, we prevented the metabolization of glucose, and thereby achieved the accumulation of growth-inhibitory glucose levels inside the cells. When a permease mediating glucose efflux is expressed in this system, the inhibitory effect is relieved proportionally to the capacity of the introduced transporter. The assay is thereby suitable for screening of transporters and quantitative analyses of their glucose efflux capacities. Moreover, by simultaneous provision of intracellular glucose and extracellular xylose, we investigated how each sugar influences the transport of the other one from the opposite side of the membrane. Thereby, we could show that the xylose transporter variant Gal2N376F is insensitive not only to extracellular but also to intracellular glucose. Considering the importance of sugar transporters in biotechnology, the assay could facilitate new developments in a variety of applications.


Assuntos
Saccharomyces cerevisiae , Xilose , Carboidratos , Glucose/metabolismo , Hexoquinase/genética , Hexoquinase/metabolismo , Maltose/metabolismo , Proteínas de Transporte de Monossacarídeos/genética , Proteínas de Transporte de Monossacarídeos/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Açúcares/metabolismo , Xilose/metabolismo
19.
Biomed Res Int ; 2022: 4668774, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35845960

RESUMO

Previous studies have shown that sevoflurane has an inhibitory effect on tumor cells. So far, the effect of sevoflurane on hepatocellular carcinoma needs to be confirmed by more studies. HOX transcript antisense intergenic RNA (HOTAIR), a long noncoding RNA (lncRNA), has been shown to enhance cancer cell proliferation and medication resistance. The inherent importance and biological function of HOTAIR in the course of lung cancer (LC) is, however, poorly unclear. HOTAIR was shown to be highly elevated in LC cells in this investigation. Impairment of function trials with sevoflurane indicated that it has anticancer effects on LC cell growth, apoptosis, and aerobic glycolysis. In a mechanistic manner, HOTAIR was related to HK2 mRNA and promoted expression and constancy. Additional research revealed that HOTAIR coupled with hexokinase 2 (HK2) mRNA and favorably controlled its stabilization in a traditional-component way. By HK2, the LC enhancement role was mediated. In summary, our data show that HOTAIR promotes the synthesis and proliferation of LC glycogen by increasing the transcription of HK2, and HOTAIR is likely to be a potential treatment for LC patients.


Assuntos
Neoplasias Hepáticas , Neoplasias Pulmonares , RNA Longo não Codificante , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Glicólise/genética , Hexoquinase/genética , Hexoquinase/metabolismo , Humanos , Neoplasias Hepáticas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sevoflurano/farmacologia
20.
Oxid Med Cell Longev ; 2022: 4476448, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35873800

RESUMO

Background: Hypothermia (H), cardioplegia (CP), and both combined (HCP) are known to be protective against myocardial ischemia reperfusion (IR) injury. Mitochondria have molecular signaling mechanisms that are associated with both cell survival and cell death. In this study, we investigated the dynamic changes in proapoptotic and prosurvival signaling pathways mediating H, CP, or HCP-induced protection of mitochondrial function after acute myocardial IR injury. Methods: Rats were divided into five groups. Each group consists of 3 subgroups based on a specific reperfusion time (5, 20, or 60 min) after a 25-min global ischemia. The time control (TC) groups were not subjected to IR but were perfused with 37 °C Krebs-Ringer's (KR) buffer, containing 4.5 mM K+, in a specific perfusion protocol that corresponded with the duration of each IR protocol. The IR group (control) was perfused for 20 min with KR, followed by 25-min global ischemia, and then KR reperfusion for 5, 20, or 60 min. The treatment groups were exposed to 17 °C H, 37 °C CP (16 mM K+), or HCP (17 °C + CP) for 5 min before ischemia and for 2 min on reperfusion before switching to 37 °C KR perfusion for the remainder of each of the reperfusion times. Cardiac function and mitochondrial redox state (NADH/FAD) were monitored online in the ex vivo hearts before, during, and after ischemia. Mitochondria were isolated at the end of each specified reperfusion time, and changes in O2 consumption, membrane potential (ΔΨ m), and Ca2+ retention capacity (CRC) were assessed using complex I and complex II substrates. In another set of hearts, mitochondrial and cytosolic fractions were isolated after a specified reperfusion time to conduct western blot assays to determine hexokinase II (HKII) and Bax binding/translocation to mitochondria, cytosolic pAkt levels, and cytochrome c (Cyto-c) release into the cytosol. Results: H and HCP were more protective of mitochondrial integrity and, concomitantly, cardiac function than CP alone; H and HCP improved post-ischemic cardiac function by (1) maintaining mitochondrial bioenergetics, (2) maintaining HKII binding to mitochondria with an increase in pAkt levels, (3) increasing CRC, and (4) decreasing Cyto-c release during reperfusion. Bax translocation/binding to mitochondria was unaffected by any treatment, regardless of cardiac functional recovery. Conclusions: Hypothermia preserved mitochondrial function and cardiac function, in part, by maintaining mitochondrial bioenergetics, by retaining HKII binding to mitochondria via upstream pAkt, and by reducing Cyto-c release independently of Bax binding to mitochondria.


Assuntos
Hipotermia , Traumatismo por Reperfusão Miocárdica , Animais , Metabolismo Energético , Hexoquinase/metabolismo , Hipotermia/metabolismo , Isquemia/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias Cardíacas/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Ratos , Reperfusão , Proteína X Associada a bcl-2/metabolismo
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