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1.
Int J Mol Sci ; 22(14)2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34299039

RESUMO

Zinc chloride is known to be effective in combatting hepatitis A virus (HAV) infection, and zinc ions seem to be especially involved in Toll-like receptor (TLR) signaling pathways. In the present study, we examined this involvement in human hepatoma cell lines using a human TLR signaling target RT-PCR array. We also observed that zinc chloride inhibited mitogen-activated protein kinase kinase 3 (MAP2K3) expression, which could downregulate HAV replication in human hepatocytes. It is possible that zinc chloride may inhibit HAV replication in association with its inhibition of MAP2K3. In that regard, this study set out to determine whether MAP2K3 could be considered a modulating factor in the development of the HAV pathogen-associated molecular pattern (PAMP) and its triggering of interferon-ß production. Because MAP2K3 seems to play a role in antiviral immunity against HAV infection, it is a promising target for drug development. The inhibition of MAP2K3 may also prevent HAV patients from developing a severe hepatitis A infection.


Assuntos
Carcinoma Hepatocelular/virologia , Cloretos/farmacologia , Hepatite A/complicações , Hepatócitos/virologia , Neoplasias Hepáticas/virologia , MAP Quinase Quinase 3/antagonistas & inibidores , Replicação Viral , Compostos de Zinco/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/enzimologia , Hepatite A/virologia , Vírus da Hepatite A/isolamento & purificação , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Interações Hospedeiro-Patógeno , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/enzimologia , Células Tumorais Cultivadas
2.
Toxicol Lett ; 349: 155-164, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34171359

RESUMO

Cytochrome P450 1A1 (CYP1A1) is a member of a subfamily of enzymes involved in the metabolism of both endogenous and exogenous substrates and the chemical activation of xenobiotics to carcinogenic derivatives. Here, the effects of nicotine, a major psychoactive compound present in cigarette smoke, on CYP1A1 expression and human hepatocellular carcinoma (HepG2) cell proliferation were investigated. Nicotine stimulated CYP1A1 expression via the transcription factors, activator protein 1, nuclear factor-kappa B, and the aryl hydrocarbon receptor (AhR) signaling pathway. Pharmacological inhibition and mutagenesis studies indicated that p38 mitogen-activated protein kinase, as well as RelA (or p65), mediated the upregulation of CYP1A1 of nicotine in HepG2 cells. The antioxidant compound, N-acetyl-cysteine, abrogated nicotine-activated production of reactive oxygen species and inhibited CYP1A1 expression by nicotine. Furthermore, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity was inhibited by diphenyleneiodonium (an NADPH oxidase inhibitor). Thus, these results demonstrated that AhR played an important role in nicotine-induced CYP1A1 expression. Additionally, liver hepatocellular carcinoma HepG2 cells treated with nicotine exhibited markedly enhanced proliferation via CYP1A1 expression and Akt activation.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinoma Hepatocelular/enzimologia , Citocromo P-450 CYP1A1/biossíntese , Neoplasias Hepáticas/enzimologia , Nicotina/toxicidade , Agonistas Nicotínicos/toxicidade , Receptores de Hidrocarboneto Arílico/metabolismo , Fator de Transcrição AP-1/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Citocromo P-450 CYP1A1/genética , Indução Enzimática , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Transdução de Sinais , Fator de Transcrição AP-1/genética , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
3.
Biochem Biophys Res Commun ; 560: 172-178, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34000466

RESUMO

Aspirin can efficiently inhibit the glycolysis and proliferation of cancer cells, however, the underlying mechanism is poorly understood. Here, we report that aspirin attenuates the glycolysis and proliferation of hepatoma cells through modulating the levels of lysine 2-hydroxyisobutyrylation (Khib) of enolase 1 (ENO1). We found that aspirin decreased the levels of glucose consumption and lactate production in hepatoma cells. Moreover, 4 mM aspirin reduced the activities of ENO1, a key enzyme of glycolysis, and decreased the levels of ENO1 Khib in the cells. Interestingly, we identified that 4 mM aspirin could decrease the levels of Khib on many proteins by using pan Khib antibody in the cells. Interestingly, the activities of ENO1 could be rescued by the transient overexpression of ENO1, but not by ENO1 mutant (K281R). Moreover, we identified that the C646, an inhibitor of p300 which is a writer of Khib, could reduce the levels of ENO1 Khib, resulting in the decrease of ENO1 activities. The treatment with PDTC, an inhibitor of NF-κB which is a target of aspirin, could work well as C646 in the cells. Both of aspirin and C646 (or PDTC) displayed a stronger effect than the single treatment in the system. Functionally, ENO1, but not ENO1 mutant (K281R), could rescue the aspirin-induced inhibition of proliferation of liver cancer cells in vitro, suggesting that ENO1K281 is involved in the aspirin-mediated inhibition of liver cancer. Our finding provides new insights into the mechanism by which aspirin attenuates the glycolysis and proliferation of hepatoma cells.


Assuntos
Antineoplásicos/farmacologia , Aspirina/farmacologia , Biomarcadores Tumorais/antagonistas & inibidores , Carcinoma Hepatocelular/tratamento farmacológico , Proteínas de Ligação a DNA/antagonistas & inibidores , Neoplasias Hepáticas/tratamento farmacológico , Fosfopiruvato Hidratase/antagonistas & inibidores , Proteínas Supressoras de Tumor/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Aspirina/uso terapêutico , Biomarcadores Tumorais/química , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Glicólise/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Lisina/metabolismo , Fosfopiruvato Hidratase/química , Fosfopiruvato Hidratase/metabolismo , Proteínas Supressoras de Tumor/química , Proteínas Supressoras de Tumor/metabolismo
4.
Cell Death Dis ; 12(6): 517, 2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-34016961

RESUMO

Metabolic reprogramming is a hallmark of malignancy. Testes-specific protease 50 (TSP50), a newly identified oncogene, has been shown to play an important role in tumorigenesis. However, its role in tumor cell metabolism remains unclear. To investigate this issue, LC-MS/MS was employed to identify TSP50-binding proteins and pyruvate kinase M2 isoform (PKM2), a known key enzyme of aerobic glycolysis, was identified as a novel binding partner of TSP50. Further studies suggested that TSP50 promoted aerobic glycolysis in HCC cells by maintaining low pyruvate kinase activity of the PKM2. Mechanistically, TSP50 promoted the Warburg effect by increasing PKM2 K433 acetylation level and PKM2 acetylation site (K433R) mutation remarkably abrogated the TSP50-induced aerobic glycolysis, cell proliferation in vitro and tumor formation in vivo. Our findings indicate that TSP50-mediated low PKM2 pyruvate kinase activity is an important determinant for Warburg effect in HCC cells and provide a mechanistic link between TSP50 and tumor metabolism.


Assuntos
Carcinoma Hepatocelular/metabolismo , Proteínas de Transporte/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas de Membrana/metabolismo , Serina Endopeptidases/metabolismo , Hormônios Tireóideos/metabolismo , Acetilação , Animais , Biomarcadores Tumorais , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Feminino , Células HEK293 , Hepatócitos/citologia , Hepatócitos/enzimologia , Hepatócitos/metabolismo , Xenoenxertos , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Oncogenes , Transfecção , Efeito Warburg em Oncologia
5.
Toxins (Basel) ; 13(4)2021 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-33918675

RESUMO

Ochratoxin A (OTA) is a mycotoxin frequently found in raw and processed foods. While it is considered a possible human carcinogen, the mechanism of action remains unclear. OTA has been shown to be hepatotoxic in both in vitro and in vivo models and oxidative stress may be one of the factors contributing to its toxicity. Hence, the effect of OTA on human hepatocellular carcinoma, HepG2 cells, was investigated on oxidative stress parameters. The cytotoxicity of OTA on HepG2 was time- and dose-dependent within a range between 0.1 and 10 µM; while 100 µM of OTA increased the intracellular reactive oxygen species (ROS) in a time-dependent manner. Additionally, the levels of glutathione (GSH) were increased by 9.7% and 11.3% at 10 and 100 nM of OTA, respectively; while OTA at 100 µM depleted GSH by 40.5% after 24 h exposure compared with the control. Finally, the mRNA level of catalase (CAT) was downregulated by 2.33-, 1.92-, and 1.82-fold after cells were treated with 1, 10, and 10 µM OTA for 24 h, respectively; which was linked to a decrease in CAT enzymatic activity. These results suggest that oxidative stress is involved in OTA-mediated toxicity in HepG2 cells.


Assuntos
Carcinoma Hepatocelular/enzimologia , Catalase/metabolismo , Neoplasias Hepáticas/enzimologia , Ocratoxinas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Catalase/genética , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação para Baixo , Regulação Enzimológica da Expressão Gênica , Glutationa/metabolismo , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Espécies Reativas de Oxigênio/metabolismo , Fatores de Tempo
6.
Arch Biochem Biophys ; 704: 108889, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33895119

RESUMO

A vast number of epidemiological, preclinical and in vitro experimental data strongly indicate the anticancer potential of calcitriol, the biologically active form of vitamin D. However, for the implementation of a vitamin D based cancer therapy the increased deactivation of calcitriol in cancer cells by overexpressed CYP24A1 hydroxylase should be suppressed. Inhibition of this enzyme expression or activity nowadays is considered as important aspect of anticancer therapeutic strategies. Herein, we investigated the impact of genistein, biochanin A, formonentin and kaempferol on the expression of the CYP24A1 gene induced by calcitriol in hepatocellular cancer cells Huh7 under normoxia (21%O2) or hypoxia (1%O2). We demonstrate that calcitriol induces CYP24A1 under normoxia and hypoxia, but this induction is significantly more potent under hypoxia, the typical microenvironment of solid tumors. In the presence of isoflavones genistein, biochanin A and formononetin, this induction is abrogated to the control levels under normoxia, while under hypoxia there is some differentiation in suppression efficacy between these compounds with genistein ≥ biochanin > formononetin. At the same time, kaempferol turned out to be completely ineffective in the suppression of CYP24A1 gene expression.


Assuntos
Carcinoma Hepatocelular/enzimologia , Flavonoides/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Hepáticas/enzimologia , Proteínas de Neoplasias/biossíntese , Vitamina D3 24-Hidroxilase/biossíntese , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos
7.
Anticancer Res ; 41(4): 1883-1893, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33813393

RESUMO

BACKGROUND/AIM: Hepatocellular carcinoma (HCC) is a highly prevalent disease and treatment is limited. Therefore, development of new therapeutic agents is urgent. The aim of this study was to investigate the in vitro and in vivo anti-cancer effects of Nardostachys jatamansi root extract (NJRE) against HCC and underlying mechanisms involved in such effects. MATERIALS AND METHODS: Effects of NJRE on viability of HCC cell lines were determined by MTT analysis and annexin/PI apoptosis assays. Expression levels of proteins in MAPK and STAT3 pathways and caspase-3 and PARP after treatment with NJRE in HCC cell lines were determined by western blotting. In a syngeneic model using mouse HCC cells Hepa1-6, inhibition of tumor formation after oral administration of NJRE was determined and expression levels of phospho-ERK and phospho-STAT3 in liver tissues were analyzed by immunohistochemical staining. RESULTS: NJRE reduced the activation of STAT3 by inhibiting the expression of ERK and finally attenuated the proliferation of HCC. CONCLUSION: NJRE has anti-cancer effects against HCC. It has potential to be used in the treatment of human HCC.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Nardostachys , Raízes de Plantas , Fator de Transcrição STAT3/metabolismo , Animais , Antineoplásicos Fitogênicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/patologia , Masculino , Camundongos Endogâmicos C57BL , Nardostachys/química , Fosforilação , Raízes de Plantas/química , Transdução de Sinais , Carga Tumoral/efeitos dos fármacos
8.
Toxicol Appl Pharmacol ; 420: 115522, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33838155

RESUMO

Baicalein is a purified flavonoid that exhibits anticancer effects in hepatocellular carcinoma (HCC). However, its underlying molecular mechanisms remain largely unclear. In this study, we found that baicalein inhibited HCC cell growth, induced apoptosis, and blocked cell cycle arrest at the S phase in vitro, as well as reduced HCC tumor volume and weight in vivo. Quantitative reverse transcriptase-PCR (qRT-PCR) results suggested that miR-3663-3p was downregulated in HCC tissues. After baicalein treatment, miR-3663-3p expression was upregulated in HCC cells. Transfection of miR-3663-3p suppressed HCC cell proliferation and colony formation, increased the proportion of apoptotic cells in vitro, and reduced the volume and weight of tumors in vivo. The results of dual-luciferase reporter assay showed that miR-3663-3p could directly bind to the 3'-UTR of SH3GL1. SH3GL1 overexpression partly reduced the growth-inhibiting effect of miR-3663-3p. Both baicalein treatment and miR-3663-3p overexpression downregulated the expression of SH3GL1 and inactivated the Erk1/2, p-NF-κB/p65, and EGFR signaling pathways. Overall, our data suggest that baicalein may act as a novel HCC suppressor, and that the miR-3663-3p/SH3GL1/EGFR/ERK/NF-κB pathway plays a vital role in HCC progression. Thus, baicalein treatment or miR-3663-3p induction may be a promising strategy for HCC therapy.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Flavanonas/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Animais , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Receptores ErbB/metabolismo , Células Hep G2 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Transdução de Sinais , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Mar Drugs ; 19(4)2021 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-33920625

RESUMO

Two new secondary metabolites, svalbamides A (1) and B (2), were isolated from a culture extract of Paenibacillus sp. SVB7 that was isolated from surface sediment from a core (HH17-1085) taken in the Svalbard archipelago in the Arctic Ocean. The combinational analysis of HR-MS and NMR spectroscopic data revealed the structures of 1 and 2 as being lipopeptides bearing 3-amino-2-pyrrolidinone, d-valine, and 3-hydroxy-8-methyldecanoic acid. The absolute configurations of the amino acid residues in svalbamides A and B were determined using the advanced Marfey's method, in which the hydrolysates of 1 and 2 were derivatized with l- and d- forms of 1-fluoro-2,4-dinitrophenyl-5-alanine amide (FDAA). The absolute configurations of 1 and 2 were completely assigned by deducing the stereochemistry of 3-hydroxy-8-methyldecanoic acid based on DP4 calculations. Svalbamides A and B induced quinone reductase activity in Hepa1c1c7 murine hepatoma cells, indicating that they represent chemotypes with a potential for functioning as chemopreventive agents.


Assuntos
Anticarcinógenos/farmacologia , Proteínas de Bactérias/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Lipopeptídeos/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Paenibacillus/metabolismo , Animais , Anticarcinógenos/isolamento & purificação , Regiões Árticas , Proteínas de Bactérias/isolamento & purificação , Carcinoma Hepatocelular/enzimologia , Linhagem Celular Tumoral , Ecossistema , Sedimentos Geológicos/microbiologia , Humanos , Lipopeptídeos/isolamento & purificação , Neoplasias Hepáticas/enzimologia , Camundongos , Estrutura Molecular , NAD(P)H Desidrogenase (Quinona)/metabolismo , Relação Estrutura-Atividade
10.
J Clin Invest ; 131(11)2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33878034

RESUMO

Rapidly growing tumors often experience hypoxia and nutrient (e.g., glucose) deficiency because of poor vascularization. Tumor cells respond to the cytotoxic effects of such stresses by inducing molecular adaptations that promote clonal selection of a more malignant tumor-initiating cell phenotype, especially in the innermost tumor regions. Here, we report a regulatory mechanism involving fucosylation by which glucose restriction promotes cancer stemness to drive drug resistance and tumor recurrence. Using hepatocellular carcinoma (HCC) as a model, we showed that restricted glucose availability enhanced the PERK/eIF2α/ATF4 signaling axis to drive fucosyltransferase 1 (FUT1) transcription via direct binding of ATF4 to the FUT1 promoter. FUT1 overexpression is a poor prognostic indicator for HCC. FUT1 inhibition could mitigate tumor initiation, self-renewal, and drug resistance. Mechanistically, we demonstrated that CD147, ICAM-1, EGFR, and EPHA2 are glycoprotein targets of FUT1, in which such fucosylation would consequently converge on deregulated AKT/mTOR/4EBP1 signaling to drive cancer stemness. Treatment with an α-(1,2)-fucosylation inhibitor sensitized HCC tumors to sorafenib, a first-line molecularly targeted drug used for advanced HCC patients, and reduced the tumor-initiating subset. FUT1 overexpression and/or CD147, ICAM-1, EGFR, and EPHA2 fucosylation may be good prognostic markers and therapeutic targets for cancer patients.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/enzimologia , Fucosiltransferases/metabolismo , Glucose/metabolismo , Neoplasias Hepáticas Experimentais/enzimologia , Proteínas de Neoplasias/metabolismo , Células-Tronco Neoplásicas/enzimologia , Animais , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Fucosiltransferases/genética , Glucose/farmacologia , Glicosilação , Células Hep G2 , Humanos , Neoplasias Hepáticas Experimentais/diagnóstico , Neoplasias Hepáticas Experimentais/genética , Camundongos , Proteínas de Neoplasias/genética , Células-Tronco Neoplásicas/patologia , Prognóstico
11.
Biochem Pharmacol ; 188: 114494, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33684390

RESUMO

Targeting the cell cycle checkpoints and DNA damage response are promising therapeutic strategies for cancer. Adavosertib is a potent inhibitor of WEE1 kinase, which plays a critical role in regulating cell cycle checkpoints. However, the effect of adavosertib on hepatocellular carcinoma (HCC) treatment, including sorafenib-resistant HCC, has not been thoroughly studied. In this study, we comprehensively investigated the efficacy and pharmacology of adavosertib in HCC therapy. Adavosertib effectively inhibited the proliferation of HCC cells in vitro and suppressed tumor growth in HCC xenografts and patient-derived xenograft (PDX) models in vivo. Additionally, adavosertib treatment effectively inhibited the motility of HCC cells by impairing pseudopodia formation. Further, we revealed that adavosertib induced DNA damage and premature mitosis entrance by disturbing the cell cycle. Thus, HCC cells accumulating DNA damage underwent mitosis without G2/M checkpoint arrest, thereby leading to mitotic catastrophe and apoptosis under adavosertib administration. Given that sorafenib resistance is common in HCC in clinical practice, we also explored the efficacy of adavosertib in sorafenib-resistant HCC. Notably, adavosertib still showed a desirable inhibitory effect on the growth of sorafenib-resistant HCC cells. Adavosertib markedly induced G2/M checkpoint arrest and cell apoptosis in a dose-dependent manner, confirming the similar efficacy of adavosertib in sorafenib-resistant HCC. Collectively, our results highlight the treatment efficacy of adavosertib in HCC regardless of sorafenib resistance, providing insights into exploring novel strategies for HCC therapy.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Proteínas de Ciclo Celular/antagonistas & inibidores , Sistemas de Liberação de Medicamentos/métodos , Neoplasias Hepáticas/tratamento farmacológico , Fenótipo , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazóis/administração & dosagem , Pirimidinonas/administração & dosagem , Animais , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/patologia , Proteínas de Ciclo Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/fisiologia , Inibidores Enzimáticos/administração & dosagem , Células Hep G2 , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Proteínas Tirosina Quinases/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
12.
Cell Death Dis ; 12(3): 253, 2021 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-33692332

RESUMO

Hepatocellular carcinoma (HCC) is a devastating malignancy without targeted therapeutic options. Our results indicated that the histone demethylase GASC1 signature is associated with later tumor stage and poorer survival in HCC patients. GASC1 depletion led to diminished HCC proliferation and tumor growth. A distinct heterogeneity in GASC1 levels was observed among HCC cell populations, predicting their inherent high or low tumor-initiating capacity. Mechanistically, GASC1 is involved in the regulation of several components of the Rho-GTPase signaling pathway including its downstream target ROCK2. GASC1 demethylase activity ensured the transcriptional repression of FBXO42, a ROCK2 protein-ubiquitin ligase, thereby inhibiting ROCK2 degradation via K63-linked poly-ubiquitination. Treatment with the GASC1 inhibitor SD70 impaired the growth of both HCC cell lines and xenografts in mice, sensitizing them to standard-of-care chemotherapy. This work identifies GASC1 as a malignant-cell-selective target in HCC, and GASC1-specific therapeutics represent promising candidates for new treatment options to control this malignancy.


Assuntos
Carcinoma Hepatocelular/enzimologia , Histona Desmetilases com o Domínio Jumonji/metabolismo , Neoplasias Hepáticas/enzimologia , Quinases Associadas a rho/metabolismo , Animais , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Proliferação de Células , Inibidores Enzimáticos/farmacologia , Estabilidade Enzimática , Proteínas F-Box/genética , Proteínas F-Box/metabolismo , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Meia-Vida , Células Hep G2 , Humanos , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , Histona Desmetilases com o Domínio Jumonji/genética , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Proteólise , Carga Tumoral , Ubiquitinação , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Int J Mol Sci ; 22(4)2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33670268

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related deaths worldwide, and its incidence is rising. HCC develops almost exclusively on the background of chronic liver inflammation, which can be caused by chronic alcohol consumption, viral hepatitis, or an unhealthy diet. The key role of chronic inflammation in the process of hepatocarcinogenesis, including in the deregulation of innate and adaptive immune responses, has been demonstrated. The inhibition of Akt (also known as Protein Kinase B) directly affects cancer cells, but this therapeutic strategy also exhibits indirect anti-tumor activity mediated by the modulation of the tumor microenvironment, as demonstrated by using Akt inhibitors AZD5363, MK-2206, or ARQ 092. Moreover, the isoforms of Akt converge and diverge in their designated roles, but the currently available Akt inhibitors fail to display an isoform specificity. Thus, selective Akt inhibition needs to be better explored in the context of HCC and its possible combination with immunotherapy. This review presents a compact overview of the current knowledge concerning the role of Akt in HCC and the effect of Akt inhibition on the HCC and liver tumor microenvironment.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Neoplasias Hepáticas/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Microambiente Tumoral , Aminopiridinas/uso terapêutico , Carcinoma Hepatocelular/enzimologia , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Imidazóis/uso terapêutico , Neoplasias Hepáticas/enzimologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico
14.
Acta Biochim Biophys Sin (Shanghai) ; 53(5): 584-592, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33772548

RESUMO

Oxaliplatin (OXA) resistance limits the efficiency of treatment for hepatocellular carcinoma (HCC). Studies have shown that the PDZ-binding kinase (PBK) plays important roles in tumors. However, the role of PBK in HCC is still a problem. In this study, we explored whether PBK is involved in the chemoresistance to OXA in HCC. Expressions of PBK in six HCC cell lines and one human hepatocytes line were determined by real-time quantitative PCR and western blot analysis. SNU-182 and HepG2 cells were chosen to induce OXA resistance. PBK was silenced or overexpressed in OXA-resistant and sensitive cell lines. Then, cell proliferation, migration, and invasion were measured by cholecystokinin-8 assay and Transwell assay, respectively. The Cancer Genome Atlas dataset showed that PBK is highly expressed in HCC and signifies poor prognosis to patient with HCC. Results showed that expression of PBK in HCC cells was significantly higher than that in THLE2 cells, and it was further increased in OXA-resistant HCC cells. Silencing of PBK promoted the sensitivity of drug-resistant HCC cells to OXA. Overexpression of PBK relieved the apoptosis induced by OXA and promoted the migration and invasion of OXA-sensitive HCC cells. Thus, this study revealed that high PBK expression is correlated with OXA resistance in HCC cells, which may provide a promising therapeutic target for treating HCC.


Assuntos
Carcinoma Hepatocelular/enzimologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Hepáticas/enzimologia , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Oxaliplatina/farmacologia , PTEN Fosfo-Hidrolase/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , PTEN Fosfo-Hidrolase/genética
15.
J Clin Invest ; 131(8)2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33690219

RESUMO

Although cancer cells are frequently faced with a nutrient- and oxygen-poor microenvironment, elevated hexosamine-biosynthesis pathway (HBP) activity and protein O-GlcNAcylation (a nutrient sensor) contribute to rapid growth of tumor and are emerging hallmarks of cancer. Inhibiting O-GlcNAcylation could be a promising anticancer strategy. The gluconeogenic enzyme phosphoenolpyruvate carboxykinase 1 (PCK1) is downregulated in hepatocellular carcinoma (HCC). However, little is known about the potential role of PCK1 in enhanced HBP activity and HCC carcinogenesis under glucose-limited conditions. In this study, PCK1 knockout markedly enhanced the global O-GlcNAcylation levels under low-glucose conditions. Mechanistically, metabolic reprogramming in PCK1-loss hepatoma cells led to oxaloacetate accumulation and increased de novo uridine triphosphate synthesis contributing to uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) biosynthesis. Meanwhile, deletion of PCK1 also resulted in AMPK-GFAT1 axis inactivation, promoting UDP-GlcNAc synthesis for elevated O-GlcNAcylation. Notably, lower expression of PCK1 promoted CHK2 threonine 378 O-GlcNAcylation, counteracting its stability and dimer formation, increasing CHK2-dependent Rb phosphorylation and HCC cell proliferation. Moreover, aminooxyacetic acid hemihydrochloride and 6-diazo-5-oxo-L-norleucine blocked HBP-mediated O-GlcNAcylation and suppressed tumor progression in liver-specific Pck1-knockout mice. We reveal a link between PCK1 depletion and hyper-O-GlcNAcylation that underlies HCC oncogenesis and suggest therapeutic targets for HCC that act by inhibiting O-GlcNAcylation.


Assuntos
Carcinoma Hepatocelular , Quinase do Ponto de Checagem 2/metabolismo , Gluconeogênese/efeitos dos fármacos , Glucose/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Neoplasias Hepáticas , Fosfoenolpiruvato Carboxiquinase (GTP)/deficiência , Acilação/efeitos dos fármacos , Acilação/genética , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Quinase do Ponto de Checagem 2/genética , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Camundongos Nus , Fosfoenolpiruvato Carboxiquinase (GTP)/metabolismo
16.
Cell Death Dis ; 12(2): 169, 2021 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-33568627

RESUMO

Cisplatin is one of the most effective chemotherapy drugs and is widely used in the treatment of cancer, including hepatocellular carcinoma (HCC) and cervical cancer, but its therapeutic benefit is limited by the development of resistance. Our previous studies demonstrated that BCAT1 promoted cell proliferation and decreased cisplatin sensitivity in HCC cells. However, the exact role and mechanism of how BCAT1 is involved in cisplatin cytotoxicity remain undefined. In this study, we revealed that cisplatin triggered autophagy in cancer cells, with an increase in BCAT1 expression. The cisplatin-induced up-regulation of BCAT1 decreased the cisplatin sensitivity by regulating autophagy through the mTOR signaling pathway. In addition, branched-chain amino acids or leucine treatment inhibited cisplatin- or BCAT1-mediated autophagy and increased cisplatin sensitivity by activating mTOR signaling in cancer cells. Moreover, inhibition of autophagy by chloroquine increased cisplatin sensitivity in vivo. Also, the knockdown of BCAT1 or the administration of leucine activated mTOR signaling, inhibited autophagy, and increased cisplatin sensitivity in cancer cells in vivo. These findings demonstrate a new mechanism, revealing that BCAT1 decreases cisplatin sensitivity in cancer cells by inducing mTOR-mediated autophagy via branched-chain amino acid leucine metabolism, providing an attractive pharmacological target to improve the effectiveness of chemotherapy.


Assuntos
Aminoácidos de Cadeia Ramificada/metabolismo , Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Cisplatino/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Serina-Treonina Quinases TOR/metabolismo , Transaminases/metabolismo , Animais , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Cloroquina/farmacologia , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Células HEK293 , Células HeLa , Células Hep G2 , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Transdução de Sinais , Transaminases/genética , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Cell Death Dis ; 12(2): 162, 2021 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-33558466

RESUMO

Hepatocellular carcinoma (HCC) is a common high-mortality cancer, mainly due to diagnostic difficulties during its early clinical stages. In this study, we aimed to identify genes that are important for HCC diagnosis and treatment, and we investigated the underlying mechanism of prognostic differences. Differentially expressed genes (DEGs) were identified by using the limma package, and receiver operating characteristic curve analysis was performed to identify diagnostic markers for HCC. Bioinformatics and clinical specimens were used to assess epithelial cell transforming 2 (ECT2) in terms of expression, prognostic value, pathways, and immune correlations. In vitro experiments were used to investigate the underlying mechanism and function of ECT2, and the results were confirmed through in vivo experiments. The integrated analysis revealed 53 upregulated DEGs, and one candidate biomarker for diagnosis (ECT2) was detected. High expression of ECT2 was found to be an independent prognostic risk factor for HCC. ECT2 expression showed a strong correlation with tumor-associated macrophages. We found that ECT2 overexpression increased the migration and proliferation of HCC cells. It also promoted the expression of PLK1, which subsequently interacted with PTEN and interfered with its nuclear translocation, ultimately enhancing aerobic glycolysis and promoting M2 macrophage polarization. M2 macrophages suppress the functions of NK cells and T cells, and this was confirmed in the in vivo experiments. Overall, ECT2 may promote the polarization of M2 macrophages by enhancing aerobic glycolysis and suppressing the functions of immune cells. ECT2 could serve as a candidate diagnostic and prognostic biomarker for HCC.


Assuntos
Carcinoma Hepatocelular/enzimologia , Proteínas de Ciclo Celular/metabolismo , Plasticidade Celular , Neoplasias Hepáticas/enzimologia , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Macrófagos Associados a Tumor/enzimologia , Apoptose , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Proteínas de Ciclo Celular/genética , Movimento Celular , Proliferação de Células , Bases de Dados Genéticas , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Glicólise , Células Hep G2 , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Invasividade Neoplásica , PTEN Fosfo-Hidrolase/genética , Fenótipo , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Transdução de Sinais , Microambiente Tumoral , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/patologia , Regulação para Cima
18.
Cancer Sci ; 112(5): 1865-1877, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33544437

RESUMO

The histone acetyltransferase MOF (KAT8) is mainly involved in the acetylation of histone H4 at lysine 16 (H4K16) and some non-histone proteins. The MOF expression level is significantly reduced in many cancers, however the biological function of MOF and its underlying mechanism are still elusive in hepatocellular carcinoma (HCC). Estrogen receptor α (ERα) has been considered as a tumor suppressor in HCC. Here, we demonstrated that MOF expression is significantly reduced in HCC samples, and is positively correlated with that of ERα. MOF interacts with ERα, and participates in acetylation of ERα at K266, K268, K299, thereby inhibiting ERα ubiquitination to maintain the stability of ERα. In addition, MOF participates in the upregulation of ERα-mediated transactivation. Depletion of MOF significantly promotes cell growth, migration, and invasion in HCC cell lines. Taken together, our results provide new insights to understand the mechanism underlying the modulation function of MOF on ERα action in HCC, suggesting that MOF might be a potential therapeutic target for HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Receptor alfa de Estrogênio/metabolismo , Histona Acetiltransferases/metabolismo , Neoplasias Hepáticas/metabolismo , Acetilação , Acetilesterase/metabolismo , Animais , Anticorpos/uso terapêutico , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Movimento Celular , Proliferação de Células , Bases de Dados Genéticas , Regulação para Baixo , Receptor alfa de Estrogênio/genética , Feminino , Xenoenxertos , Histona Acetiltransferases/deficiência , Histonas/metabolismo , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Lisina/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Invasividade Neoplásica , Transdução de Sinais , Ativação Transcricional , Ubiquitinação , Regulação para Cima
19.
Eur J Cancer ; 147: 63-73, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33618200

RESUMO

OBJECTIVE: The mechanisms underlying the contribution of primary tumour to pre-metastatic niche formation remains largely unknown in hepatocellular carcinoma (HCC). We previously reported that the released LOXL2 from HCC cells under higher stiffness stimulation facilitated the formation of lung pre-metastatic niche. Here, we further clarified the pathological role of LOXL2 in promoting lung pre-metastatic niche formation and lung metastasis occurrence in HCC and its relevant molecular mechanism. METHODS: Using two different animal models and an in vitro system of mechanically tuneable gel mirroring lung tissue stiffness, we explored the underlying mechanism of LOXL2 in pre-metastatic niche formation. RESULTS: We applied tail vein injection of CM-LV-LOXL2-OEsimulating tumour-released soluble factors to induce lung pre-metastatic niche formation and found that the injected LOXL2 remarkably enhanced CD11b+/CD45+ bone marrow-derived cells (BMDCs) recruitment and fibronectin expression in lung. Subsequently, LOXL2-overexpressed xenograft HCC models validated that tumour-secreted LOXL2 significantly promoted the occurrence of pulmonary metastasis. In vitro, LOXL2 and LOXL2-caused matrix stiffening not only obviously upregulated the expressions of MMP9 and fibronectin in lung fibroblasts, but also evidently increased the number of adherent HCC cells and the expression of chemokine CXCL12. The activation of PI3K-AKT pathway mediated LOXL2-upregulated fibronectin. HCC patients in High-LOXL2 group had higher ratio of tumour recurrence than HCC patients in Low-LOXL2 group, supporting a significance of LOXL2 in HCC progression and unfavourable outcome. CONCLUSION: Primary tumour-released LOXL2 promotes lung pre-metastatic niche formation and lung metastasis occurrence. LOXL2-caused matrix stiffening synergistically regulates lung pre-metastatic niche formation. Targeting LOXL2-induced lung pre-metastatic niche may be a novel intervention approach against HCC metastasis.


Assuntos
Aminoácido Oxirredutases/metabolismo , Carcinoma Hepatocelular/enzimologia , Neoplasias Hepáticas/enzimologia , Neoplasias Pulmonares/enzimologia , Microambiente Tumoral , Aminoácido Oxirredutases/genética , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/secundário , Linhagem Celular Tumoral , Quimiocina CXCL12/metabolismo , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Feminino , Fibroblastos/enzimologia , Fibroblastos/patologia , Fibronectinas/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
20.
Am J Physiol Gastrointest Liver Physiol ; 320(4): G543-G556, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33406006

RESUMO

Tumor stroma and microenvironment have been shown to affect hepatocellular carcinoma (HCC) growth, with activated hepatic stellate cells (HSC) as a major contributor in this process. Recent evidence suggests that the energy sensor adenosine monophosphate-activated kinase (AMPK) may mediate a series of essential processes during carcinogenesis and HCC progression. Here, we investigated the effect of different HCC cell lines with known TP53 or CTNBB1 mutations on primary human HSC activation, proliferation, and AMPK activation. We show that conditioned media obtained from multiple HCC cell lines differently modulate human hepatic stellate cell (hHSC) proliferation and hHSC AMPK activity in a paracrine manner. Pharmacological treatment of hHSC with AICAR and Compound C inhibited the HCC-induced proliferation/activation of hHSC through AMPK-dependent and AMPK-independent mechanisms, which was further confirmed using mouse embryonic fibroblasts (MEFs) deficient of both catalytic AMPKα isoforms (AMPKα1/α2-/-) and wild type (wt) MEF. Both compounds induced S-phase cell-cycle arrest and, in addition, AICAR inhibited the mTORC1 pathway by inhibiting phosphorylation of 4E-BP1 and S6 in hHSC and wt MEF. Data mining of the Cancer Genome Atlas (TCGA) and the Liver Cancer (LICA-FR) showed that AMPKα1 (PRKAA1) and AMPKα2 (PRKAA2) expression differed depending on the mutation (TP53 or CTNNB1), tumor grading, and G1-G6 classification, reflecting the heterogeneity in human HCC. Overall, we provide evidence that AMPK modulating pharmacological agents negatively modulate HCC-induced hHSC activation and may therefore provide a novel approach to target the mutual, tumor-promoting interactions between hHSC and HCC.NEW & NOTEWORTHY HCC is marked by genetic heterogeneity and activated hepatic stellate cells (HSC) are considered key players during HCC development. The paracrine effect of different HCC cell lines on the activation of primary hHSC was accompanied by differential AMPK activation depending on the HCC line used. Pharmacological treatment inhibited the HCC-induced hHSC activation through AMPK-dependent and AMPK-independent mechanisms. This heterogenic effect on HCC-induced AMPK activation was confirmed by data mining TCGA and LICA-FR databases.


Assuntos
Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Aminoimidazol Carboxamida/análogos & derivados , Carcinoma Hepatocelular/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Ativadores de Enzimas/farmacologia , Células Estreladas do Fígado/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Comunicação Parácrina , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Ribonucleotídeos/farmacologia , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Aminoimidazol Carboxamida/farmacologia , Animais , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Meios de Cultivo Condicionados , Bases de Dados Genéticas , Ativação Enzimática , Células Hep G2 , Células Estreladas do Fígado/enzimologia , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Mutação , Fosforilação , Transdução de Sinais , Microambiente Tumoral , Proteína Supressora de Tumor p53/genética , beta Catenina/genética
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