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1.
Int J Mol Sci ; 22(6)2021 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-33804063

RESUMEN

Besides its insulinotropic actions on pancreatic ß cells, neuroprotective activities of glucagon-like peptide-1 (GLP-1) have attracted attention. The efficacy of a GLP-1 receptor (GLP-1R) agonist exendin-4 (Ex-4) for functional repair after sciatic nerve injury and amelioration of diabetic peripheral neuropathy (DPN) has been reported; however, the underlying mechanisms remain unclear. In this study, the bioactivities of Ex-4 on immortalized adult rat Schwann cells IFRS1 and adult rat dorsal root ganglion (DRG) neuron-IFRS1 co-culture system were investigated. Localization of GLP-1R in both DRG neurons and IFRS1 cells were confirmed using knockout-validated monoclonal Mab7F38 antibody. Treatment with 100 nM Ex-4 significantly enhanced survival/proliferation and migration of IFRS1 cells, as well as stimulated the movement of IFRS1 cells toward neurites emerging from DRG neuron cell bodies in the co-culture with the upregulation of myelin protein 22 and myelin protein zero. Because Ex-4 induced phosphorylation of serine/threonine-specific protein kinase AKT in these cells and its effects on DRG neurons and IFRS1 cells were attenuated by phosphatidyl inositol-3'-phosphate-kinase (PI3K) inhibitor LY294002, Ex-4 might act on both cells to activate PI3K/AKT signaling pathway, thereby promoting myelination in the co-culture. These findings imply the potential efficacy of Ex-4 toward DPN and other peripheral nerve lesions.


Asunto(s)
Neuropatías Diabéticas/tratamiento farmacológico , Exenatida/farmacología , Péptido 1 Similar al Glucagón/genética , Receptor del Péptido 1 Similar al Glucagón/genética , Animales , Movimiento Celular/genética , Supervivencia Celular/genética , Cromonas/farmacología , Técnicas de Cocultivo , Neuropatías Diabéticas/genética , Neuropatías Diabéticas/patología , Exenatida/genética , Ganglios Espinales/citología , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/patología , Receptor del Péptido 1 Similar al Glucagón/agonistas , Humanos , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Morfolinas/farmacología , Vaina de Mielina/genética , Vaina de Mielina/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/genética , Ratas , Células de Schwann/citología , Células de Schwann/efectos de los fármacos , Células de Schwann/metabolismo , Nervio Ciático/lesiones
2.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-33799501

RESUMEN

The growth hormone (GH)/insulin-like growth factor I (IGF-I) axis is involved in metabolic control. Malnutrition reduces IGF-I and modifies the thermogenic capacity of brown adipose tissue (BAT). Leptin has effects on the GH/IGF-I axis and the function of BAT, but its interaction with IGF-I and the mechanisms involved in the regulation of thermogenesis remains unknown. We studied the GH/IGF-I axis and activation of IGF-I-related signaling and metabolism related to BAT thermogenesis in chronic central leptin infused (L), pair-fed (PF), and control rats. Hypothalamic somatostatin mRNA levels were increased in PF and decreased in L, while pituitary GH mRNA was reduced in PF. Serum GH and IGF-I concentrations were decreased only in PF. In BAT, the association between suppressor of cytokine signaling 3 and the IGF-I receptor was reduced, and phosphorylation of the IGF-I receptor increased in the L group. Phosphorylation of Akt and cyclic AMP response element binding protein and glucose transporter 4 mRNA levels were increased in L and mRNA levels of uncoupling protein-1 (UCP-1) and enzymes involved in lipid anabolism reduced in PF. These results suggest that modifications in UCP-1 in BAT and changes in the GH/IGF-I axis induced by negative energy balance are dependent upon leptin levels.


Asunto(s)
Tejido Adiposo Pardo/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Hormona del Crecimiento/genética , Factor I del Crecimiento Similar a la Insulina/genética , Leptina/farmacología , Termogénesis/efectos de los fármacos , Tejido Adiposo Pardo/metabolismo , Animales , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Metabolismo Energético/genética , Transportador de Glucosa de Tipo 4/genética , Transportador de Glucosa de Tipo 4/metabolismo , Hormona del Crecimiento/metabolismo , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Inyecciones Intraventriculares , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Fosforilación/efectos de los fármacos , Hipófisis/efectos de los fármacos , Hipófisis/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Somatostatina/genética , Somatostatina/metabolismo , Proteína 3 Supresora de la Señalización de Citocinas/genética , Proteína 3 Supresora de la Señalización de Citocinas/metabolismo , Termogénesis/genética , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
3.
Int J Mol Sci ; 22(6)2021 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-33804169

RESUMEN

Glioblastoma multiforme (GBM) is a malignant primary brain tumor with poor patient prognosis. Although the standard treatment of GBM is surgery followed by chemotherapy and radiotherapy, often a small portion of surviving tumor cells acquire therapeutic resistance and become more aggressive. Recently, altered kinase expression and activity have been shown to determine metabolic flux in tumor cells and metabolic reprogramming has emerged as a tumor progression regulatory mechanism. Here we investigated novel kinase-mediated metabolic alterations that lead to acquired GBM radioresistance and malignancy. We utilized transcriptomic analyses within a radioresistant GBM orthotopic xenograft mouse model that overexpresses the dual specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3). We find that within GBM cells, radiation exposure induces DYRK3 expression and DYRK3 regulates mammalian target of rapamycin complex 1 (mTORC1) activity through phosphorylation of proline-rich AKT1 substrate 1 (PRAS40). We also find that DYRK3 knockdown inhibits dynamin-related protein 1 (DRP1)-mediated mitochondrial fission, leading to increased oxidative phosphorylation (OXPHOS) and reduced glycolysis. Importantly, enforced DYRK3 downregulation following irradiation significantly impaired GBM cell migration and invasion. Collectively, we suggest DYRK3 suppression may be a novel strategy for preventing GBM malignancy through regulating mitochondrial metabolism.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Dinaminas/genética , Glioblastoma/radioterapia , Proteínas Serina-Treonina Quinasas/genética , Proteínas Tirosina Quinasas/genética , Animales , Línea Celular Tumoral , Proliferación Celular/genética , Proliferación Celular/efectos de la radiación , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Glioblastoma/genética , Glioblastoma/patología , Humanos , Ratones , Mitocondrias/genética , Mitocondrias/patología , Mitocondrias/efectos de la radiación , Fosforilación Oxidativa/efectos de la radiación , Proteínas Proto-Oncogénicas c-akt/genética , Tolerancia a Radiación/genética , Ensayos Antitumor por Modelo de Xenoinjerto
4.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-33805714

RESUMEN

Trifluoperazine (TFP), an antipsychotic drug approved by the Food and Drug Administration, has been show to exhibit anti-cancer effects. Pulmonary arterial hypertension (PAH) is a devastating disease characterized by a progressive obliteration of small pulmonary arteries (PAs) due to exaggerated proliferation and resistance to apoptosis of PA smooth muscle cells (PASMCs). However, the therapeutic potential of TFP for correcting the cancer-like phenotype of PAH-PASMCs and improving PAH in animal models remains unknown. PASMCs isolated from PAH patients were exposed to different concentrations of TFP before assessments of cell proliferation and apoptosis. The in vivo therapeutic potential of TFP was tested in two preclinical models with established PAH, namely the monocrotaline and sugen/hypoxia-induced rat models. Assessments of hemodynamics by right heart catheterization and histopathology were conducted. TFP showed strong anti-survival and anti-proliferative effects on cultured PAH-PASMCs. Exposure to TFP was associated with downregulation of AKT activity and nuclear translocation of forkhead box protein O3 (FOXO3). In both preclinical models, TFP significantly lowered the right ventricular systolic pressure and total pulmonary resistance and improved cardiac function. Consistently, TFP reduced the medial wall thickness of distal PAs. Overall, our data indicate that TFP could have beneficial effects in PAH and support the view that seeking new uses for old drugs may represent a fruitful approach.


Asunto(s)
Fármacos Cardiovasculares/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Hipertensión Pulmonar/tratamiento farmacológico , Hipoxia/prevención & control , Miocitos del Músculo Liso/efectos de los fármacos , Trifluoperazina/farmacología , Animales , Antipsicóticos/farmacología , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Reposicionamiento de Medicamentos , Femenino , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/metabolismo , Hemodinámica/efectos de los fármacos , Humanos , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/fisiopatología , Hipoxia/inducido químicamente , Hipoxia/genética , Hipoxia/fisiopatología , Indoles/administración & dosificación , Monocrotalina/administración & dosificación , Músculo Liso Vascular/citología , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/citología , Miocitos del Músculo Liso/metabolismo , Cultivo Primario de Células , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Arteria Pulmonar/citología , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/metabolismo , Pirroles/administración & dosificación , Ratas , Ratas Sprague-Dawley , Survivin/genética , Survivin/metabolismo
5.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-33805770

RESUMEN

Pre-mRNA splicing plays an important role in muscle function and diseases. The RNA binding motif 20 (RBM20) is a splicing factor that is predominantly expressed in muscle tissues and primarily regulates pre-mRNA splicing of Ttn, encoding a giant muscle protein titin that is responsible for muscle function and diseases. RBM20-mediated Ttn splicing has been mostly studied in heart muscle, but not in skeletal muscle. In this study, we investigated splicing specificity in different muscle types in Rbm20 knockout rats and hormonal effects on RBM20-mediated splicing both in cellulo and in vivo studies. The results revealed that RBM20 is differentially expressed across muscles and RBM20-mediated splicing is muscle-type specific. In the presence of RBM20, Ttn splicing responds to hormones in a muscle-type dependent manner, while in the absence of RBM20, Ttn splicing is not affected by hormones. In differentiated and undifferentiated C2C12 cells, RBM20-mediated splicing in response to hormonal effects is mainly through genomic signaling pathway. The knowledge gained from this study may help further understand muscle-specific gene splicing in response to hormone stimuli in different muscle types.


Asunto(s)
Conectina/genética , Músculo Esquelético/efectos de los fármacos , Mioblastos/efectos de los fármacos , Precursores del ARN/genética , Empalme del ARN , Proteínas de Unión al ARN/genética , Animales , Antitiroideos/farmacología , Línea Celular , Conectina/metabolismo , Cruzamientos Genéticos , Femenino , Humanos , Masculino , Músculo Esquelético/citología , Músculo Esquelético/metabolismo , Mioblastos/citología , Mioblastos/metabolismo , Especificidad de Órganos , Propiltiouracilo/farmacología , Proteínas Proto-Oncogénicas c-akt/genética , Precursores del ARN/metabolismo , Proteínas de Unión al ARN/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Estreptozocina/farmacología , Triyodotironina/farmacología
6.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-33805784

RESUMEN

Hepatocellular carcinoma (HCC) frequently shows early invasion into blood vessels as well as intrahepatic metastasis. Innovations of novel small-molecule agents to block HCC invasion and subsequent metastasis are urgently needed. Moscatilin is a bibenzyl derivative extracted from the stems of a traditional Chinese medicine, orchid Dendrobium loddigesii. Although moscatilin has been reported to suppress tumor angiogenesis and growth, the anti-metastatic property of moscatilin has not been elucidated. The present results revealed that moscatilin inhibited metastatic behavior of HCC cells without cytotoxic fashion in highly invasive human HCC cell lines. Furthermore, moscatilin significantly suppressed the activity of urokinase plasminogen activator (uPA), but not matrix metalloproteinase (MMP)-2 and MMP-9. Interestingly, moscatilin-suppressed uPA activity was through down-regulation the protein level of uPA, and did not impair the uPA receptor and uPA inhibitory molecule (PAI-1) expressions. Meanwhile, the mRNA expression of uPA was inhibited via moscatilin in a concentration-dependent manner. In addition, the expression of phosphorylated Akt, rather than ERK1/2, was inhibited by moscatilin treatment. The expression of phosphor-IκBα, and -p65, as well as κB-luciferase activity were also repressed after moscatilin treatment. Transfection of constitutively active Akt (Myr-Akt) obviously restored the moscatilin-inhibited the activation of NF-κB and uPA, and cancer invasion in HCC cells. Taken together, these results suggest that moscatilin impedes HCC invasion and uPA expression through the Akt/NF-κB signaling pathway. Moscatilin might serve as a potential anti-metastatic agent against the disease progression of human HCC.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Compuestos de Bencilo/farmacología , Movimiento Celular/efectos de los fármacos , FN-kappa B/genética , Proteínas Proto-Oncogénicas c-akt/genética , Activador de Plasminógeno de Tipo Uroquinasa/genética , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Embrión de Pollo , Membrana Corioalantoides/irrigación sanguínea , Membrana Corioalantoides/efectos de los fármacos , Factor 4E Eucariótico de Iniciación/genética , Factor 4E Eucariótico de Iniciación/metabolismo , Regulación Neoplásica de la Expresión Génica , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Hepatocitos/patología , Humanos , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , FN-kappa B/antagonistas & inhibidores , FN-kappa B/metabolismo , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Neovascularización Patológica/prevención & control , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Quinasas S6 Ribosómicas 70-kDa/genética , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Activador de Plasminógeno de Tipo Uroquinasa/antagonistas & inhibidores , Activador de Plasminógeno de Tipo Uroquinasa/metabolismo
7.
Nat Commun ; 12(1): 2245, 2021 04 14.
Artículo en Inglés | MEDLINE | ID: mdl-33854067

RESUMEN

Breast cancer is a heterogeneous pathology, but the genomic basis of its variability remains poorly understood in populations other than Caucasians. Here, through DNA and RNA portraits we explored the molecular features of breast cancers in a set of Hispanic-Mexican (HM) women and compared them to public multi-ancestry datasets. HM patients present an earlier onset of the disease, particularly in aggressive clinical subtypes, compared to non-Hispanic women. The age-related COSMIC signature 1 was more frequent in HM women than in those from other ancestries. We found the AKT1E17K hotspot mutation in 8% of the HM women and identify the AKT1/PIK3CA axis as a potentially druggable target. Also, HM luminal breast tumors present an enhanced immunogenic phenotype compared to Asiatic and Caucasian tumors. This study is an initial effort to include patients from Hispanic populations in the research of breast cancer etiology and biology to further understand breast cancer disparities.


Asunto(s)
Neoplasias de la Mama/etnología , Neoplasias de la Mama/etiología , Hispanoamericanos/genética , Americanos Mexicanos/genética , Adulto , Anciano , Neoplasias de la Mama/metabolismo , Fosfatidilinositol 3-Quinasa Clase I/genética , Femenino , Humanos , Persona de Mediana Edad , Mutación , Proteínas Proto-Oncogénicas c-akt/genética , Secuenciación del Exoma Completo
8.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 46(1): 18-24, 2021 Jan 28.
Artículo en Inglés, Chino | MEDLINE | ID: mdl-33678632

RESUMEN

OBJECTIVES: To investigate the effects of propofol on the proliferation and invasion of glioma U87 cells and to explore the possible anti-tumor mechanisms. METHODS: The glioma U87 cells was divided into a blank group, a positive control group, and the propofol groups (1.00, 2.00 or 5.00 mmol/L). Cell counting kit-8 (CCK-8) was used to detect cell proliferation; Transwell method was used to detect the effect of propofol on invasion and migration of U87 cells; real-time PCR was used to detect the expression of microRNA-134 (miR-134); Western blotting was used to detect the expression levels of reproduction-related protein Ki-67, invasion-related protein metalloproteinase-2 (MMP-2), metalloproteinase-9 (MMP-9) and phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) signaling pathway-related protein. RESULTS: Compared with the blank group, the proliferation, invasion and migration capacity of U87 cells were reduced in the positive control group and the propofol groups after 48 hours (all P<0.05), along with the decreased expression of Ki-67, MMP-2 and MMP-9 and the ratio of p-PI3K/PI3K and p-Akt/Akt (all P<0.05), while the level of miR-134 was increased significantly (P<0.05). Compared with the positive control group and the 1.00 mmol/L propofol-treated group, the proliferation, invasion and migration capacity of U87 cells, the expression of Ki-67, MMP-2 and MMP-9, and the ratio of p-PI3K/PI3K and p-Akt/Akt was decreased significantly after 48 hours (all P<0.05), while the level of miR-134 was increased significantly in the 2.00 and 5.00 mmol/L propofol-treated groups (both P<0.05). Compared with the 2.00 mmol/L propofol-treated group, the proliferation, invasion and migration capacity of U87 cells, the expression of Ki-67, MMP-2 and MMP-9, and the ratio of p-PI3K/PI3K and p-Akt/Akt was decreased significantly after 48 hours in the 5.00 mmol/L propofol-treated group (all P<0.05), while the level of miR-134 was increased significantly (P<0.05). CONCLUSIONS: Propofol can decrease the proliferation rate, and the invasion and migration abilities of U87 cells, which may be achieved by up-regulation of miR-134 and suppression of PI3K/Akt signaling pathway.


Asunto(s)
Glioma , MicroARNs , Propofol , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Glioma/genética , Humanos , Metaloproteinasa 2 de la Matriz/genética , MicroARNs/genética , Fosfatidilinositol 3-Quinasas/genética , Propofol/farmacología , Proteínas Proto-Oncogénicas c-akt/genética
9.
Mol Med Rep ; 23(5)2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33760200

RESUMEN

Proliferative vitreoretinopathy (PVR) is a disease leading to the formation of contractile preretinal membranes (PRMs) and is one of the leading causes of blindness. Connective tissue growth factor (CTGF) has been identified as a possible key determinant of progressive tissue fibrosis and excessive scarring. Therefore, the present study investigated the role and mechanism of action of CTGF in PVR. Immunohistochemical staining was performed to detect the expression of CTGF, fibronectin and collagen type III in PRMs from patients with PVR. The effects and mechanisms of recombinant human CTGF and its upstream regulator, TGF­ß1, on epithelial­mesenchymal transition (EMT) and the synthesis of extracellular matrix (ECM) by retinal pigment epithelium (RPE) cells were investigated using reverse transcription­quantitative PCR, western blotting and a [3H]proline incorporation assay. The data indicated that CTGF, fibronectin and collagen type III were highly expressed in PRMs. In vitro, CTGF significantly decreased the expression of the epithelial markers ZO­1 and E­cadherin and increased that of the mesenchymal markers fibronectin, N­cadherin and α­smooth muscle actin in a concentration­dependent manner. Furthermore, the expression of the ECM protein collagen type III was upregulated by CTGF. However, the trends in expression for the above­mentioned markers were reversed after knocking down CTGF. The incorporation of [3H]proline into RPE cells was also increased by CTGF. In addition, 8­Bromoadenosine cAMP inhibited CTGF­stimulated collagen synthesis and transient transfection of RPE cells with a CTGF antisense oligonucleotide inhibited TGF­ß1­induced collagen synthesis. The phosphorylation of PI3K and AKT in RPE cells was promoted by CTGF and TGF­ß1 and the latter promoted the expression of CTGF. The results of the present study indicated that CTGF may promote EMT and ECM synthesis in PVR via the PI3K/AKT signaling pathway and suggested that targeting CTGF signaling may have a therapeutic or preventative effect on PVR.


Asunto(s)
Factor de Crecimiento del Tejido Conjuntivo/genética , Transición Epitelial-Mesenquimal/genética , Pigmentos Retinianos/genética , Factor de Crecimiento Transformador beta1/genética , Vitreorretinopatía Proliferativa/genética , Western Blotting , Movimiento Celular/genética , Matriz Extracelular/genética , Fibronectinas/genética , Humanos , Fosfatidilinositol 3-Quinasas/genética , Fosforilación , Proteínas Proto-Oncogénicas c-akt/genética , Epitelio Pigmentado de la Retina/crecimiento & desarrollo , Epitelio Pigmentado de la Retina/metabolismo , Transducción de Señal/genética , Vitreorretinopatía Proliferativa/patología
10.
Crit Rev Oncol Hematol ; 160: 103284, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33675910

RESUMEN

A systematic review (SR) and meta-analysis were conducted to determine the prevalence of PI3K-AKT-mTOR signaling pathway mutations in patients with head and neck cancer (HNC). Overall, 105 studies comprising 8630 patients and 1306 mutations were selected. The estimated mutations prevalence was 13 % for PIK3CA (95 % confidence interval [CI] = 11-14; I2 = 82 %; p < 0.0001), 4% for PTEN (95 % CI = 3-5; I2 = 55 %; p < 0.0001), 3% for MTOR (95 % CI = 2-4; I2 = 5%; p = 0.40), and 2% for AKT (95 % CI = 1-2; I2 = 50 %; p = 0.0001). We further stratified the available data of the participants according to risk factors and tumor characteristics, including HPV infection, tobacco use, alcohol exposure, TNM stage, and histological tumor differentiation, and performed subgroup analysis. We identified significant associations between PI3K-AKT-mTOR pathway-associated mutations and advanced TNM stage (odds ratio [OR] = 0.20; 95 % CI = 0.09-0.44; I² = 71 %; p = 0.0001) and oropharyngeal HPV-positive tumors and PIK3CA mutations (OR = 17.48; 95 % CI = 4.20-72.76; I² = 69 %; p < 0.0002). No associations were found between alcohol and tobacco exposure, and tumor differentiation grade. This SR demonstrated that the PI3K-AKT-mTOR pathway emerges as a potential prognostic factor and could offer a molecular basis for future studies on therapeutic targeting in HNC patients.


Asunto(s)
Neoplasias de Cabeza y Cuello , Fosfatidilinositol 3-Quinasas , Neoplasias de Cabeza y Cuello/epidemiología , Neoplasias de Cabeza y Cuello/genética , Humanos , Mutación , Fosfatidilinositol 3-Quinasas/genética , Prevalencia , Proteínas Proto-Oncogénicas c-akt/genética , Serina-Treonina Quinasas TOR/genética
11.
Int J Mol Sci ; 22(4)2021 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-33668685

RESUMEN

Many long noncoding RNAs have been implicated in tumorigenesis and chemoresistance; however, the underlying mechanisms are not well understood. We investigated the role of PRKAR1B-AS2 long noncoding RNA in ovarian cancer (OC) and chemoresistance and identified potential downstream molecular circuitry underlying its action. Analysis of The Cancer Genome Atlas OC dataset, in vitro experiments, proteomic analysis, and a xenograft OC mouse model were implemented. Our findings indicated that overexpression of PRKAR1B-AS2 is negatively correlated with overall survival in OC patients. Furthermore, PRKAR1B-AS2 knockdown-attenuated proliferation, migration, and invasion of OC cells and ameliorated cisplatin and alpelisib resistance in vitro. In proteomic analysis, silencing PRKAR1B-AS2 markedly inhibited protein expression of PI3K-110α and abrogated the phosphorylation of PDK1, AKT, and mTOR, with no significant effect on PTEN. The RNA immunoprecipitation detected a physical interaction between PRKAR1B-AS2 and PI3K-110α. Moreover, PRKAR1B-AS2 knockdown by systemic administration of 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine nanoparticles loaded with PRKAR1B-AS2-specific small interfering RNA enhanced cisplatin sensitivity in a xenograft OC mouse model. In conclusion, PRKAR1B-AS2 promotes tumor growth and confers chemoresistance by modulating the PI3K/AKT/mTOR pathway. Thus, targeting PRKAR1B-AS2 may represent a novel therapeutic approach for the treatment of OC patients.


Asunto(s)
Carcinogénesis/metabolismo , Resistencia a Antineoplásicos , Neoplasias Ováricas/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Largo no Codificante/metabolismo , ARN Neoplásico/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Línea Celular Tumoral , Supervivencia Celular , Femenino , Humanos , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/genética , ARN Largo no Codificante/genética , ARN Neoplásico/genética , Serina-Treonina Quinasas TOR/genética
12.
Int J Mol Sci ; 22(4)2021 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-33673180

RESUMEN

Bam32 (B cell adaptor molecule of 32 kDa) functions in the immune responses of various leukocytes. However, the role of neutrophil Bam32 in inflammation is entirely unknown. Here, we determined the role of Bam32 in chemokine CXCL2-induced neutrophil chemotaxis in three mouse models of neutrophil recruitment. By using intravital microscopy in the mouse cremaster muscle, we found that transmigrated neutrophil number, neutrophil chemotaxis velocity, and total neutrophil chemotaxis distance were increased in Bam32-/- mice when compared with wild-type (WT) mice. In CXCL2-induced mouse peritonitis, the total emigrated neutrophils were increased in Bam32-/- mice at 2 but not 4 h. The CXCL2-induced chemotaxis distance and migration velocity of isolated Bam32-/- neutrophils in vitro were increased. We examined the activation of small GTPases Rac1, Rac2, and Rap1; the levels of phospho-Akt2 and total Akt2; and their crosstalk with Bam32 in neutrophils. The deficiency of Bam32 suppressed Rap1 activation without changing the activation of Rac1 and Rac2. The pharmacological inhibition of Rap1 by geranylgeranyltransferase I inhibitor (GGTI298) increased WT neutrophil chemotaxis. In addition, the deficiency of Bam32, as well as the inhibition of Rap1 activation, increased the levels of CXCL2-induced Akt1/2 phosphorylation at Thr308/309 in neutrophils. The inhibition of Akt by SH-5 attenuated CXCL2-induced adhesion and emigration in Bam32-/- mice. Together, our results reveal that Bam32 has a suppressive role in chemokine-induced neutrophil chemotaxis by regulating Rap1 activation and that this role of Bam32 in chemokine-induced neutrophil recruitment relies on the activation of PI3K effector Akt.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Quimiocinas/metabolismo , Lipoproteínas/metabolismo , Infiltración Neutrófila , Neutrófilos/metabolismo , Transducción de Señal , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Quimiocinas/genética , Lipoproteínas/genética , Ratones , Ratones Noqueados , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas de Unión al GTP rho/genética , Proteínas de Unión al GTP rho/metabolismo
13.
Life Sci ; 273: 119297, 2021 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-33689686

RESUMEN

Stress-induced gastritis is a common problem in the intensive care unit. Zeaxanthin (ZE), a non-provitamin A carotenoid has been known to exert antioxidant and anti-inflammatory effects. In this study, we examined the effect of ZE on water avoidance stress (WAS)-induced gastritis in rats. 24 Sprague' Dawley male rats were divided into four groups; control, ZE, WAS and WAS+ZE. In the stressed rats, treatment with ZE effectively downregulated the gastric levels of total oxidant status (TOS), myeloperoxidase (MPO) and malondialdehyde (MDA), with significant upregulation of the antioxidant enzymes' activities and gastric levels of prostagladin-E2 (PGE2) as compared to the untreated stressed one. As noticed in the present study, ZE significantly decrease the gastric levels of interleukin-1 ß (IL-1ß) and IL-6 as well as suppression of nuclear transcription factor kappa-B (NF-κB) immunohistochemical expression together with upregulation of trefoil factor-1 (TFF-1) gene expression. Moreover, in the untreated WAS-induced gastritis group, gastrin and corticosterone levels were significantly increased together with upregulation of the gene expression of hypoxia inducible factor-1α (HIF-1α), matrix metalloproteinase-9 (MMP-9), PI3K, Akt and JNK in the gastric tissues, which significantly improved by ZE administration. These all positive effects of ZE reflected on reduction of microscopic gastric mucosal damage and inflammatory cell infiltration with improvement of ulcer score. Our results discover that ZE has a new gastroprotective effect against stress-induced gastritis in rats, primarily through its antioxidative and anti-inflammatory effects, which are expressed in the regulation of the MMP-9 and HIF-1α signaling pathways.


Asunto(s)
Biomarcadores/análisis , Gastritis/tratamiento farmacológico , Regulación de la Expresión Génica/efectos de los fármacos , Sustancias Protectoras/farmacología , Estrés Fisiológico , Zeaxantinas/farmacología , Animales , Antioxidantes/metabolismo , Citocinas/metabolismo , Gastritis/etiología , Gastritis/metabolismo , Gastritis/patología , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , MAP Quinasa Quinasa 4/genética , MAP Quinasa Quinasa 4/metabolismo , Masculino , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Estrés Oxidativo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Sprague-Dawley , Factor Trefoil-1/genética , Factor Trefoil-1/metabolismo
14.
Life Sci ; 274: 119253, 2021 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-33647270

RESUMEN

AIM: Exercise is cardioprotective, though optimal interventions are unclear. We assessed duration dependent effects of exercise on myocardial ischemia-reperfusion (I-R) injury, kinase signaling and gene expression. METHODS: Responses to brief (2 day; 2EX), intermediate (7 and 14 day; 7EX and 14EX) and extended (28 day; 28EX) voluntary wheel running (VWR) were studied in male C57Bl/6 mice. Cardiac function, I-R tolerance and survival kinase signaling were assessed in perfused hearts. KEY FINDINGS: Mice progressively increased running distances and intensity, from 2.4 ± 0.2 km/day (0.55 ± 0.04 m/s) at 2-days to 10.6 ± 0.4 km/day (0.72 ± 0.06 m/s) after 28-days. Myocardial mass and contractility were modified at 14-28 days VWR. Cardioprotection was not 'dose-dependent', with I-R tolerance enhanced within 7 days and not further improved with greater VWR duration, volume or intensity. Protection was associated with AKT, ERK1/2 and GSK3ß phosphorylation, with phospho-AMPK selectively enhanced with brief VWR. Gene expression was duration-dependent: 7 day VWR up-regulated glycolytic (Pfkm) and down-regulated maladaptive remodeling (Mmp2) genes; 28 day VWR up-regulated caveolar (Cav3), mitochondrial biogenesis (Ppargc1a, Sirt3) and titin (Ttn) genes. Interestingly, I-R tolerance in 2EX/2SED groups improved vs. groups subjected to longer sedentariness, suggesting transient protection on transition to housing with running wheels. SIGNIFICANCE: Cardioprotection is induced with as little as 7 days VWR, yet not enhanced with further or faster running. This protection is linked to survival kinase phospho-regulation (particularly AKT and ERK1/2), with glycolytic, mitochondrial, caveolar and myofibrillar gene changes potentially contributing. Intriguingly, environmental enrichment may also protect via similar kinase regulation.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Regulación de la Expresión Génica , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Isquemia Miocárdica/prevención & control , Condicionamiento Físico Animal , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Quinasas Activadas por AMP/genética , Animales , Glucógeno Sintasa Quinasa 3 beta/genética , Sistema de Señalización de MAP Quinasas , Masculino , Ratones , Ratones Endogámicos C57BL , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/patología , Fosforilación , Proteínas Proto-Oncogénicas c-akt/genética
15.
Life Sci ; 274: 119354, 2021 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-33737087

RESUMEN

AIMS: Gigantol is a bibenzyl compound isolated from orchids of the genus Dendrobium. Gigantol has been demonstrated to possess various pharmacologic (including anticancer) effects. Cisplatin (DDP) has been used and studied as the first-line agent for breast cancer (BC) treatment. Often, its efficacy is jeopardized due to intolerance and organ toxicity. We investigated if gigantol could enhance the anticancer effects of DDP in BC cells and its underlying mechanism of action. MAIN METHODS: The potential pathway of gigantol in BC cells was detected by network-pharmacology and molecular-docking studies. The proliferation and apoptosis of BC cell lines were measured by the MTT assay, colony formation, Hoechst-33342 staining, and flow cytometry. Protein expression was measured by western blotting. KEY FINDINGS: Gigantol could inhibit proliferation of BC cells and enhance DDP-induced apoptosis. According to the results of western blotting, gigantol reinforced DDP-induced anticancer effects through downregulation of the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway in BC cells. The effects were consistent with those of the pathway inhibitor LY294002. SIGNIFICANCE: Our data might provide new insights into the underlying antitumor effect of gigantol in BC cells. This enhancement effect in the combination of gigantol and DDP may provide many therapeutic benefits in clinical treatment regimens against BC.


Asunto(s)
Bibencilos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Cisplatino/farmacología , Sinergismo Farmacológico , Guayacol/análogos & derivados , Fosfatidilinositol 3-Quinasas/química , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Antineoplásicos/farmacología , Apoptosis , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular , Femenino , Regulación Neoplásica de la Expresión Génica , Guayacol/farmacología , Humanos , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Células Tumorales Cultivadas
16.
Molecules ; 26(5)2021 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-33668689

RESUMEN

Rapamycin is an antifungal drug with antitumor activity and acts inhibiting the mTOR complex. Due to drug antitumor potential, the aim of this study was to evaluate its effect on a preclinical model of primary mammary gland tumors and their metastases from female dogs. Four cell lines from our cell bank, two from primary canine mammary tumors (UNESP-CM1, UNESP-CM60) and two metastases (UNESP-MM1, and UNESP-MM4) were cultured in vitro and investigated for rapamycin IC50. Then, cell lines were treated with rapamycin IC50 dose and mRNA and protein were extracted in treated and non-treated cells to perform AKT, mTOR, PTEN and 4EBP1 gene expression and global proteomics by mass spectrometry. MTT assay demonstrated rapamycin IC50 dose for all different tumor cells between 2 and 10 µM. RT-qPCR from cultured cells, control versus treated group and primary tumor cells versus metastatic tumor cells, did not shown statistical differences. In proteomics were found 273 proteins in all groups, and after data normalization 49 and 92 proteins were used for statistical analysis for comparisons between control versus rapamycin treatment groups, and metastasis versus primary tumor versus metastasis rapamycin versus primary tumor rapamycin, respectively. Considering the two statistical analysis, four proteins, phosphoglycerate mutase, malate dehydrogenase, l-lactate dehydrogenase and nucleolin were found in decreased abundance in the rapamycin group and they are related with cellular metabolic processes and enhanced tumor malignant behavior. Two proteins, dihydrolipoamide dehydrogenase and superoxide dismutase, also related with metabolic processes, were found in higher abundance in rapamycin group and are associated with apoptosis. The results suggested that rapamycin was able to inhibit cell growth of mammary gland tumor and metastatic tumors cells in vitro, however, concentrations needed to reach the IC50 were higher when compared to other studies.


Asunto(s)
Antibióticos Antineoplásicos/farmacología , Neoplasias Mamarias Animales/tratamiento farmacológico , Proteómica , Sirolimus/farmacología , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Perros , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Neoplasias Mamarias Animales/metabolismo , Neoplasias Mamarias Animales/patología , Espectrometría de Masas , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Células Tumorales Cultivadas
17.
Mol Med Rep ; 23(5)2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33760104

RESUMEN

Gastric cancer (GC) is a common malignant tumor in the digestive system, which presents without specific symptoms. Circular RNAs (circRNAs) play important roles in tumor progression and cellular functions; however, the relationship between GC and hsa_circ_0072309 remains unclear. The aim of the present study was to investigate the molecular mechanisms of hsa_circ_0072309 and the role that hsa_circ_0072309 plays in proliferation, invasion and migration of GC cells. The expression of hsa_circ_0072309 was evaluated using reverse transcription­quantitative PCR. A series of functional experiments were performed to study the role that hsa_circ_0072309 has in survival and metastasis of GC cells. In the present study, hsa_circ_0072309 was downregulated in GC cell lines and its overexpression inhibited the proliferation, migration and invasion of GC cells. In addition, hsa_circ_0072309 overexpression induced activation of the peroxisome proliferator­activated receptor γ (PPARγ)/PTEN pathway and inhibition of PI3K/AKT signaling. Moreover, pioglitazone, a PPARγ agonist, strengthened the effects of abundant hsa_circ_0072309 on the proliferative, migratory and invasive capabilities of GC cells, while GW9662, a PPARγ antagonist, abolished the effects of hsa_circ_0072309 overexpression on cell proliferation, migration and invasion. The present findings suggested that hsa_circ_0072309 inhibited proliferation, invasion and migration of gastric cancer cells via the inhibition of PI3K/AKT signaling by activating the PPARγ/PTEN signaling pathway. Targeting hsa_circ_0072309 may be an innovative therapeutic strategy for the treatment of GC.


Asunto(s)
PPAR gamma/genética , Fosfohidrolasa PTEN/genética , ARN Circular/genética , Neoplasias Gástricas/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/genética , Transducción de Señal/genética , Neoplasias Gástricas/patología
18.
Mol Med Rep ; 23(5)2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33760114

RESUMEN

Steroid­induced avascular necrosis of the femoral head (SANFH) is a common orthopaedic disease that is difficult to treat. The present study investigated the effects of total flavonoids of Rhizoma drynariae (TFRD) on SANFH and explored its underlying mechanisms. The SANFH rat model was induced by intramuscular injection of lipopolysaccharides and methylprednisolone. Osteoblasts were isolated from the calvariae of neonatal rats and then cultured with dexamethasone (Dex). TFRD was used in vitro and in vivo, respectively. Haematoxylin and eosin staining was used to assess the pathological changes in the femoral head. Terminal deoxynucleotidyl transferase­mediated deoxyuridine triphosphate nick end labelling assay and flow cytometry were conducted to detect apoptosis of osteoblasts. The 2',7'­dichlorofluorescein­diacetate staining method was used to detect reactive oxygen species (ROS) levels in osteoblasts and the 3­(4,5­dimethylthiazol­2­yl)­2,5­diphenyltetrazolium bromide assay was used to detect osteoblast proliferation. The expression of caspase­3, Bax, Bcl­2, VEGF, runt­related transcription factor 2 (RUNX2), osteoprotegerin (OPG), osteocalcin (OCN), receptor activator of nuclear factor κB ligand (RANKL) and phosphoinositide 3­kinase (PI3K)/AKT pathway related­proteins were detected via western blotting. It was found that TFRD reduced the pathological changes, inhibited apoptosis, increased the expression of VEGF, RUNX2, OPG and OCN, decreased RANKL expression and activated the PI3K/AKT pathway in SANFH rats. TFRD promoted proliferation, inhibited apoptosis and reduced ROS levels by activating the PI3K/AKT pathway in osteoblasts. In conclusion, TFRD protected against SANFH in a rat model. In addition, TFRD protected osteoblasts from Dex­induced damage through the PI3K/AKT pathway. The findings of the present study may contribute to find an effective treatment for the management of SANFH.


Asunto(s)
Flavonoides/farmacología , Osteonecrosis/tratamiento farmacológico , Extractos Vegetales/farmacología , Polypodiaceae/química , Animales , Proliferación Celular/efectos de los fármacos , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Modelos Animales de Enfermedad , Cabeza Femoral/patología , Flavonoides/química , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Osteoblastos/efectos de los fármacos , Osteogénesis por Distracción/métodos , Osteonecrosis/inducido químicamente , Osteonecrosis/patología , Osteoprotegerina/genética , Fosfatidilinositol 3-Quinasas/genética , Extractos Vegetales/química , Proteínas Proto-Oncogénicas c-akt/genética , Ligando RANK/genética , Ratas , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Esteroides/efectos adversos
19.
Mol Med Rep ; 23(5)2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33760204

RESUMEN

Cisplatin (DDP)­based chemotherapy is a standard treatment for cervical cancer, although chemotherapy resistance remains a major concern. Hypoxia­inducible factor­2 α (HIF­2α) plays an important role in chemotherapy resistance. MicroRNAs (miRs) can inhibit gene expression by binding to the 3'­untranslated region of the target gene. The authors' previous study showed that miR­519d­3p plays an important role in the regulation of HIF­2α expression under hypoxic conditions in cervical cancer. However, the function and regulatory mechanisms of the miR­519d­3p/HIF­2α axis in DDP­resistance in cervical cancer are not fully understood. Therefore, the aim of the present study was to investigate whether the miR­519d­3p/HIF­2α axis increased DDP resistance by regulating the PI3K/AKT signaling pathway. It was found that the expression of miR­519d­3p was lower in DDP­resistant cervical cancer cells (CaSki/DDP and HeLa/DDP) compared with CaSki and HeLa cells under hypoxic conditions. Additionally, miR­519d­3p overexpression decreased the IC50 value in CaSki/DDP and HeLa/DDP cells, and inhibited HIF­2α protein expression and the PI3K/AKT signaling pathway under hypoxic conditions. Furthermore, it was demonstrated that HIF­2α overexpression reduced the effect of miR­519d­3p overexpression on HeLa/DDP and CaSki/DDP cells. Moreover, the present results suggested that HIF­2α overexpression increased the IC50 value in CaSki/DDP and HeLa/DDP cells. It was also found that HIF­2α overexpression reduced the effect of miR­519d­3p overexpression on the PI3K/AKT signaling pathway. Therefore, the present results indicated that the miR­519d­3p/HIF­2α axis increased DDP resistance of cervical cancer cells by suppressing the PI3K/AKT signaling pathway under hypoxic conditions.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Cisplatino/farmacología , MicroARNs/genética , Neoplasias del Cuello Uterino/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cisplatino/efectos adversos , Resistencia a Antineoplásicos/genética , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HeLa , Humanos , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/genética , Transducción de Señal/efectos de los fármacos , Hipoxia Tumoral/genética , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patología
20.
Nat Commun ; 12(1): 1940, 2021 03 29.
Artículo en Inglés | MEDLINE | ID: mdl-33782411

RESUMEN

Metabolic enzymes and metabolites display non-metabolic functions in immune cell signalling that modulate immune attack ability. However, whether and how a tumour's metabolic remodelling contributes to its immune resistance remain to be clarified. Here we perform a functional screen of metabolic genes that rescue tumour cells from effector T cell cytotoxicity, and identify the embryo- and tumour-specific folate cycle enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2). Mechanistically, MTHFD2 promotes basal and IFN-γ-stimulated PD-L1 expression, which is necessary for tumourigenesis in vivo. Moreover, IFN-γ stimulates MTHFD2 through the AKT-mTORC1 pathway. Meanwhile, MTHFD2 drives the folate cycle to sustain sufficient uridine-related metabolites including UDP-GlcNAc, which promotes the global O-GlcNAcylation of proteins including cMYC, resulting in increased cMYC stability and PD-L1 transcription. Consistently, the O-GlcNAcylation level positively correlates with MTHFD2 and PD-L1 in pancreatic cancer patients. These findings uncover a non-metabolic role for MTHFD2 in cell signalling and cancer biology.


Asunto(s)
Aminohidrolasas/genética , Antígeno B7-H1/genética , Carcinogénesis/genética , Regulación Neoplásica de la Expresión Génica , Metilenotetrahidrofolato Deshidrogenasa (NADP)/genética , Enzimas Multifuncionales/genética , Neoplasias Pancreáticas/genética , Procesamiento Proteico-Postraduccional , Linfocitos T Citotóxicos/inmunología , Aminohidrolasas/antagonistas & inhibidores , Aminohidrolasas/inmunología , Animales , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Carcinogénesis/inmunología , Carcinogénesis/patología , Línea Celular Tumoral , Embrión de Mamíferos , Fibroblastos/inmunología , Fibroblastos/patología , Ácido Fólico/inmunología , Ácido Fólico/metabolismo , Humanos , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Diana Mecanicista del Complejo 1 de la Rapamicina/inmunología , Metilenotetrahidrofolato Deshidrogenasa (NADP)/antagonistas & inhibidores , Metilenotetrahidrofolato Deshidrogenasa (NADP)/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Desnudos , Enzimas Multifuncionales/antagonistas & inhibidores , Enzimas Multifuncionales/inmunología , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Cultivo Primario de Células , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/inmunología , Proteínas Proto-Oncogénicas c-myc/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/inmunología , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/inmunología , Transducción de Señal , Linfocitos T Citotóxicos/patología , Carga Tumoral , Escape del Tumor , Uridina Difosfato N-Acetilglucosamina/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
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