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1.
Pharmacogenomics J ; 24(2): 5, 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38378770

RESUMO

OBJECTIVE: To explore the role of p300 in the context of paclitaxel (PTX) resistance in triple-negative breast cancer (TNBC) cells, focusing on its interaction with the phosphoenolpyruvate carboxykinase 1 (PCK1)/adenosine monophosphate-activated protein kinase (AMPK) pathway. METHODS: The expression of p300 and PCK1 at the messenger ribonucleic acid (mRNA) level was detected using a quantitative polymerase chain reaction. The GeneCards and GEPIA databases were used to investigate the relationship between p300 and PCK1. The MDA-MB-231/PTX cell line, known for its PTX resistance, was chosen to understand the specific role of p300 in such cells. The Lipofectamine™ 3000 reagent was used to transfer the p300 small interfering RNA and the overexpression of PCK1 plasmid into MDA-MB-231/PTX. The expression levels of p300, PCK1, 5'AMPK and phosphorylated AMPK (p-AMPK) were determined using the western blot test. RESULTS: In TNBC cancer tissue, the expression of p300 was increased compared with TNBC paracancerous tissue (P < 0.05). In the MDA-MB-231 cell line of TNBC, the expression of p300 was lower than in the PTX-resistant TNBC cells (MDA-MB-231/PTX) (P < 0.05). The PCK1 expression was decreased in the TNBC cancer tissue compared with TNBC paracancerous tissue, and the PCK1 expression was reduced in MDA-MB-231/PTX than in MDA-MB-231 (P < 0.05) indicating that PCK1 was involved in the resistance function. Additionally, p-AMPK was decreased in MDA-MB-231/PTX compared with MDA-MB-231 (P < 0.05). The adenosine triphosphate (ATP) level was also detected and was significantly lower in MDA-MB-231/PTX than in MDA-MB-231 (P < 0.05). Additionally, cell proliferation increased significantly in MDA-MB-231/PTX at 48 and 72 h (P < 0.05) suggesting that MDA-MB-231/PTX cells obtained the resistance function which was associated with AMPK and ATP level. When p300 was inhibited, p-AMPK and ATP levels elevated in MDA-MB-231/PTX (P < 0.05). When PCK1 was suppressed, the ATP consumption rate decreased, and cell proliferation increased (P < 0.05). However, there were no changes in p300. CONCLUSIONS: In MDA-MB-231/PTX, p300 can inhibit p-AMPK and ATP levels by inhibiting PCK1 expression. Our findings suggest that targeting p300 could modulate the PCK1/AMPK axis, offering a potential therapeutic avenue for overcoming PTX resistance in TNBC.


Assuntos
Paclitaxel , Neoplasias de Mama Triplo Negativas , Humanos , Trifosfato de Adenosina/uso terapêutico , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas Quinases Ativadas por AMP/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células , Peptídeos e Proteínas de Sinalização Intracelular/genética , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Fosfoenolpiruvato Carboxiquinase (GTP)/genética , Fosfoenolpiruvato Carboxiquinase (GTP)/metabolismo , Fosfoenolpiruvato Carboxiquinase (GTP)/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Regulação para Cima
2.
J Physiol Biochem ; 73(1): 89-98, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27785616

RESUMO

Whole body cytosolic phosphoenolpyruvate carboxykinase knockout (PEPCK-C KO) mice die early after birth with profound hypoglycemia therefore masking the role of PEPCK-C in adult, non-gluconeogenic tissues where it is expressed. To investigate whether PEPCK-C deletion in the liver was critically responsible for the hypoglycemic phenotype, we reexpress this enzyme in the liver of PEPCK-C KO pups by early postnatal administration of PEPCK-C-expressing adenovirus. This maneuver was sufficient to partially rescue hypoglycemia and allow the pups to survive and identifies the liver as a critical organ, and hypoglycemia as the critical pathomechanism, leading to early postnatal death in the whole-body PEPCK-C knockout mice. Pathology assessment of survivors also suggest a possible role for PEPCK-C in lung maturation and muscle metabolism.


Assuntos
Erros Inatos do Metabolismo dos Carboidratos/veterinária , Hipoglicemia/prevenção & controle , Hepatopatias/veterinária , Fígado/enzimologia , Pulmão/metabolismo , Músculo Esquelético/metabolismo , Fosfoenolpiruvato Carboxiquinase (GTP)/deficiência , Fosfoenolpiruvato Carboxiquinase (GTP)/metabolismo , Animais , Animais Recém-Nascidos , Encéfalo/enzimologia , Encéfalo/metabolismo , Encéfalo/patologia , Erros Inatos do Metabolismo dos Carboidratos/enzimologia , Erros Inatos do Metabolismo dos Carboidratos/fisiopatologia , Erros Inatos do Metabolismo dos Carboidratos/terapia , Cruzamentos Genéticos , Técnicas de Transferência de Genes , Gluconeogênese , Heterozigoto , Hipoglicemia/etiologia , Hipoglicemia/metabolismo , Hipoglicemia/patologia , Gotículas Lipídicas/metabolismo , Gotículas Lipídicas/patologia , Metabolismo dos Lipídeos , Lipidoses/etiologia , Fígado/metabolismo , Fígado/patologia , Hepatopatias/enzimologia , Hepatopatias/fisiopatologia , Hepatopatias/terapia , Pulmão/enzimologia , Pulmão/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Esquelético/enzimologia , Músculo Esquelético/patologia , Neurônios/enzimologia , Neurônios/metabolismo , Neurônios/patologia , Fosfoenolpiruvato Carboxiquinase (GTP)/genética , Fosfoenolpiruvato Carboxiquinase (GTP)/uso terapêutico , Proteínas Recombinantes/metabolismo
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