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1.
Int J Med Sci ; 18(7): 1618-1627, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33746578

RESUMEN

Hypoxia affects proliferation, differentiation, as well as death of cardiomyocyte, and plays an important role in the development of myocardial ischemia. However, the detailed mechanisms through which hypoxia regulates cardiomyocyte ferroptosis have not been explored. In this study, we revealed that hypoxia suppresses the proliferation, migration, and erastin-induced ferroptosis of H9c2 cells. First, we confirmed the upregulation of SENP1 in H9c2 cells cultured under hypoxic conditions. Through adenovirus-mediated SENP1 gene transfection, we demonstrated that SENP1 overexpression could enhance H9c2 cell proliferation and migration while also protecting H9c2 cells from erastin-induced ferroptosis. Furthermore, through immunoprecipitation and western blotting, we confirmed that SENP1 mediated deSUMOylation of HIF-1α and ACSL4 in H9c2 cells. In conclusion, this study describes the underlying mechanism through which hypoxia upregulates SENP1 expression, in turn protecting against ferroptosis via the regulation of HIF-1α and ACSL4 deSUMOylation. Our findings provide a theoretical foundation for the development of novel therapeutics for ischemic heart diseases.


Asunto(s)
Hipoxia de la Célula/genética , Cisteína Endopeptidasas/metabolismo , Ferroptosis/genética , Miocitos Cardíacos/patología , Animales , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Coenzima A Ligasas/metabolismo , Cisteína Endopeptidasas/genética , Ferroptosis/efectos de los fármacos , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Isquemia Miocárdica/patología , Miocitos Cardíacos/efectos de los fármacos , Piperazinas/farmacología , Ratas , Transducción de Señal/genética , Sumoilación/genética , Regulación hacia Arriba
2.
Biochem Biophys Res Commun ; 526(2): 431-438, 2020 05 28.
Artículo en Inglés | MEDLINE | ID: mdl-32228887

RESUMEN

The mRNA precursor 3'-end modification factor NUDT21 is a major regulator of 3'UTR shortening and an important component of pre-mRNA cleavage and polyadenylation. However, its role in pathologic progress of small cell lung cancer (SCLC) remains unclear. In this study, we observed that NUDT21 expression is downregulated in SCLC tissues. Hypoxia-induced down-regulation of NUDT21 through HIF-1α. NUDT21 shRNA transduction promotes proliferation and inhibits apoptosis of A549 cells. NUDT21 inhibition also promotes tumor growth in a mouse xenograft model. Furthermore, we clarified that HIF-1α mediated NUDT21 downregulation which altered the expression patterns of two isoforms of GLS1, GAC and KGA. These results link the hypoxic tumor environments to aberrant glutamine metabolism which is important for cellular energy in SCLC cells. Therefore, NUDT21 could be considered as a potential target for the treatment of SCLC.


Asunto(s)
Factor de Especificidad de Desdoblamiento y Poliadenilación/metabolismo , Glutaminasa/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Empalme del ARN/genética , Carcinoma Pulmonar de Células Pequeñas/genética , Carcinoma Pulmonar de Células Pequeñas/patología , Células A549 , Proliferación Celular/genética , Células Cultivadas , Glutaminasa/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , MicroARNs/genética , Poliadenilación , Carcinoma Pulmonar de Células Pequeñas/metabolismo
3.
Biochem Biophys Res Commun ; 515(3): 448-454, 2019 07 30.
Artículo en Inglés | MEDLINE | ID: mdl-31160087

RESUMEN

Endothelial cell death is linked to vascular diseases such as atherosclerosis and tissue ischemia. miRNA-17-92 (miR-17-92) is a multiple functional oncogenic miRNA cluster which plays vital roles in tumor angiogenesis and tissue development. However, its role in regulation of endothelial cell ferroptosis remains unclear. In this study, we revealed that miR-17-92 protects endothelial HUVEC cells from erastin-induced ferroptosis. miR-17-92 overexpression significantly reduced erastin-induced growth inhibition and ROS generation of HUVEC cells. Furthermore, Zinc lipoprotein A20, a validated target of miR-17-92, was identified as a novel regulator of endothelial cell ferroptosis. Lentivirus mediated A20 overexpression increased ROS generation and enhanced erastin-induced ferroptosis, whereas A20 knockdown inhibited erastin-induced ferroptosis. Mechanistic studies revealed that erastin-induced ferroptosis is associated with GPX4 downregulation and ACSL4 upregulation. miR-17-92 overexpression or A20 inhibition increased the ACSL4 expression in HUVEC cells. A20 was identified to directly with and regulate ACSL4 expression by immunoprecipitation. It suggests that the A20-ACSL4 axis plays important roles in erastin-induced endothelial ferroptosis. In conclusion, this study revealed a novel mechanism through which miR-17-92 protects endothelial cells from erastin-induced ferroptosis by targeting the A20-ACSL4 axis.


Asunto(s)
Coenzima A Ligasas/metabolismo , Citoprotección , Ferroptosis/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , MicroARNs/metabolismo , Piperazinas/farmacología , Transducción de Señal , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/metabolismo , Proliferación Celular/efectos de los fármacos , Citoprotección/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/citología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , MicroARNs/genética , Transducción de Señal/efectos de los fármacos
4.
BMC Biotechnol ; 19(1): 23, 2019 04 24.
Artículo en Inglés | MEDLINE | ID: mdl-31014302

RESUMEN

BACKGROUND: The gene transduction efficiency of adenovirus to hematopoietic cells, especially T lymphocytes, is needed to be improved. The purpose of this study is to improve the transduction efficiency of T lymphocytes by using fiber-modified human adenovirus 5 (HAdV-5) vectors. RESULTS: Four fiber-modified human adenovirus 5 (HAdV-5) vectors were investigated to transduce hematopoietic cells. F35-EG or F11p-EG were HAdV-35 or HAdV-11p fiber pseudotyped HAdV-5, and HR-EG or CR-EG vectors were generated by incorporating RGD motif to the HI loop or to the C-terminus of F11p-EG fiber. All vectors could transduce more than 90% of K562 or Jurkat cells at an multiplicity of infection (MOI) of 500 viral particle per cell (vp/cell). All vectors except HR-EG could transduce nearly 90% cord blood CD34+ cells or 80% primary human T cells at the MOI of 1000, and F11p-EG showed slight superiority to F35-EG and CR-EG. Adenoviral vectors transduced CD4+ T cells a little more efficiently than they did to CD8+ T cells. These vectors showed no cytotoxicity at an MOI as high as 1000 vp/cell because the infected and uninfected T cells retained the same CD4/CD8 ratio and cell growth rate. CONCLUSIONS: HAdV-11p fiber pseudotyped HAdV-5 could effectively transduce human T cells when human EF1a promoter was used to control the expression of transgene, suggesting its possible application in T cell immunocellular therapy.


Asunto(s)
Adenovirus Humanos/genética , Técnicas de Transferencia de Gen/normas , Vectores Genéticos/genética , Linfocitos T/metabolismo , Proteínas de la Cola de los Virus/genética , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/virología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/virología , Proliferación Celular/genética , Terapia Genética/métodos , Células HL-60 , Humanos , Células Jurkat , Células K562 , Linfocitos T/virología , Transducción Genética/normas , Transgenes/genética , Células U937 , Proteínas de la Cola de los Virus/metabolismo
5.
Molecules ; 24(8)2019 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-30995808

RESUMEN

Ginkgo biloba L., an ancient dioecious gymnosperm, is now cultivated worldwide for landscaping and medical purposes. A novel biflavonoid-amentoflavone 7''-O-ß-D-glucopyranoside (1)-and four known biflavonoids were isolated and identified from the male flowers of Ginkgo. The anti-proliferative activities of five biflavonoids were evaluated on different cancer lines. Bilobetin (3) and isoginkgetin (4) exhibited better anti-proliferative activities on different cancer lines. Their effects were found to be cell-specific and in a dose and time dependent manner for the most sensitive HeLa cells. The significant morphological changes validated their anticancer effects in a dose-dependent manner. They were capable of arresting the G2/M phase of the cell cycle, inducing the apoptosis of HeLa cells dose-dependently and activating the proapoptotic protein Bax and the executor caspase-3. Bilobetin (3) could also inhibit the antiapoptotic protein Bcl-2. These might be the mechanism underlying their anti-proliferation. In short, bilobetin (3) and isoginkgetin (4) might be the early lead compounds for new anticancer agents.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Biflavonoides/farmacología , Flores/química , Ginkgo biloba/química , Extractos Vegetales/farmacología , Antineoplásicos Fitogénicos/química , Biflavonoides/química , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Humanos , Espectroscopía de Resonancia Magnética , Estructura Molecular , Extractos Vegetales/química
6.
Biochem Biophys Res Commun ; 499(1): 44-51, 2018 04 30.
Artículo en Inglés | MEDLINE | ID: mdl-29551679

RESUMEN

Ferroptosis is an iron- and oxidative-dependent form of regulated cell death and may play important roles in maintaining myocardium homeostasis and pathology of cardiovascular diseases. Currently, the regulatory roles of lipid signals in regulating cardiomyocytes ferroptosis has not been explored. In this study, we show that ENPP2, as a lipid kinase involved in lipid metabolism, protects against erastin-induced ferroptosis in cardiomyocytes. The classical ferroptosis inducer erastin remarkably inhibits the growth which could be rescued by the small molecule Fer-1 in H9c2 cells. Adenovirus mediated ENPP2 overexpression modestly promotes migration and proliferation and significantly inhibits erastin-induced ferroptosis of H9c2 cells. ENPP2 overexpression leads to increase the LPA level in supernatant of H9c2 cells. H9c2 cells express the LPAR1, LPAR3, LPAR4 and LPAR5 receptors. The supernatant of ENPP2 transduced cardiomyocytes could protects the cells from erastin-induced ferroptosis of H9c2 cells. Furthermore, we observed that ENPP2 overexpression regulates ferroptosis-associated gene GPX4, ACSL4 and NRF2 expression and modulates MAPK and AKT signal in H9c2 cells. Collectively, these findings demonstrated that ENPP2/LPA protects cardiomyocytes from erastin-induced ferroptosis through modulating GPX4, ACSL4 and NRF2 expression and enhancing AKT survival signal.


Asunto(s)
Apoptosis/efectos de los fármacos , Citotoxinas/toxicidad , Hierro/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Hidrolasas Diéster Fosfóricas/genética , Piperazinas/toxicidad , Animales , Apoptosis/genética , Línea Celular , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Coenzima A Ligasas/genética , Coenzima A Ligasas/metabolismo , Regulación de la Expresión Génica , Vectores Genéticos/química , Vectores Genéticos/metabolismo , Glutatión Peroxidasa/genética , Glutatión Peroxidasa/metabolismo , Lentivirus/genética , Lentivirus/metabolismo , Miocitos Cardíacos/citología , Miocitos Cardíacos/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Hidrolasas Diéster Fosfóricas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Receptores del Ácido Lisofosfatídico/genética , Receptores del Ácido Lisofosfatídico/metabolismo , Transducción de Señal , Transducción Genética
7.
Exp Cell Res ; 351(1): 74-81, 2017 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-28043832

RESUMEN

MicroRNAs (miRNAs) regulate the hypoxia-induced erythroid differentiation of hematopoietic cells. In this study, we identified that miR-486 was a rapid response miRNA to hypoxia in erythroleukemia TF-1 cells. Hypoxia exposure increased both intracellular and miR-486 levels of TF-1 cells. Ectopic miR-486 expression enhanced the growth and erythroid differentiation of TF-1 cells, whereas miR-486 inhibition suppressed their growth and erythroid differentiation. Treatment of TF-1 and cord blood CD34+ cells with exogenous containing miR-486 resulted in an increase of intracellular miR-486 level and enhanced erythroid differentiation. Furthermore, we identified that Sirt1 is a miR-486 target gene which modulates hypoxia-induced erythroid differentiation of TF-1 cells. Thus we identified a novel miRNA regulatory network that contributes to hypoxia-induced erythroid differentiation of hematopoietic cells.


Asunto(s)
Células Precursoras Eritroides/citología , Eritropoyesis , Leucemia Eritroblástica Aguda/metabolismo , MicroARNs/genética , Sirtuina 1/genética , Hipoxia de la Célula , Línea Celular Tumoral , Células Cultivadas , Células Precursoras Eritroides/metabolismo , Humanos , Oxígeno/metabolismo , Sirtuina 1/metabolismo
8.
Blood ; 125(8): 1302-13, 2015 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-25515961

RESUMEN

MicroRNAs (miRNAs) are key regulators of hematopoietic cell differentiation and may contribute to altered growth of leukemic stem cells. Using microarray-based miRNA profiling, we found that miRNA 486 (miR-486) is significantly upregulated in chronic myeloid leukemia (CML) compared with normal CD34(+) cells, particularly in the megakaryocyte-erythroid progenitor population. miR-486-5p expression increased during erythroid differentiation of both CML and normal CD34(+) cells. Ectopic miR-486-5p expression enhanced in vitro erythroid differentiation of normal CD34(+) cells, whereas miR-486-5p inhibition suppressed normal CD34(+) cell growth in vitro and in vivo and inhibited erythroid differentiation and erythroid cell survival. The effects of miR-486-5p on hematopoietic cell growth and survival are mediated at least in part via regulation of AKT signaling and FOXO1 expression. Using gene expression and bioinformatics analysis, together with functional screening, we identified several novel miR-486-5p target genes that may modulate erythroid differentiation. We further show that increased miR-486-5p expression in CML progenitors is related to both kinase-dependent and kinase-independent mechanisms. Inhibition of miR-486-5p reduced CML progenitor growth and enhanced apoptosis following imatinib treatment. In conclusion, our studies reveal a novel role for miR-486-5p in regulating normal hematopoiesis and of BCR-ABL-induced miR-486-5p overexpression in modulating CML progenitor growth, survival, and drug sensitivity.


Asunto(s)
Proliferación Celular/genética , Resistencia a Antineoplásicos/genética , Eritropoyesis/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Células Progenitoras de Megacariocitos y Eritrocitos/fisiología , MicroARNs/fisiología , Animales , Diferenciación Celular/genética , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Células HEK293 , Células Hep G2 , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Ratones Transgénicos
9.
Biochem Biophys Res Commun ; 470(3): 670-677, 2016 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-26801559

RESUMEN

MicroRNA-486 (miR-486) was first identified from human fetal liver cDNA library and validated as a regulator of hematopoiesis. Its roles in regulating the biological function of bone marrow-derived mesnechymal stem cells (BM-MSCs) under hypoxia have not been explored yet. In this study, we demonstrated that exposure to hypoxia upregulates miR-486 expression in BM-MSCs. Lentivirus-mediated overexpression of miR-486 resulted in increase of hepatocyte growth factor (HGF) and vascular endothelial growth factor(VEGF) in both mRNA and protein levels. MiR-486 expression also promotes proliferation and reduces apoptosis of BM-MSCs. Whereas MiR-486 knockdown downregulated the secretion of HGF and VEGF and induced apoptosis of BM-MSCs. Furthermore, PTEN-PI3K/AKT signaling was validated to be involved in changes of BM-MSC biological functions regulated by miR-486. These results suggested that MiR-486 mediated the hypoxia-induced angiogenic activity and promoted the proliferation and survival of BM-MSCs through regulating PTEN-PI3K/AKT signaling. These findings might provide a novel understanding of effective therapeutic strategy for hypoxic-ischemic diseases.


Asunto(s)
Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/fisiología , MicroARNs/metabolismo , Neovascularización Fisiológica/fisiología , Proteína Oncogénica v-akt/metabolismo , Oxígeno/metabolismo , Proteínas Angiogénicas/metabolismo , Diferenciación Celular/fisiología , Hipoxia de la Célula/fisiología , Movimiento Celular/fisiología , Supervivencia Celular/fisiología , Células Cultivadas , Regulación de la Expresión Génica/fisiología , Humanos , Transducción de Señal/fisiología
10.
Biochem Biophys Res Commun ; 471(4): 459-65, 2016 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-26898802

RESUMEN

Hypoxia provokes metabolism misbalance, mitochondrial dysfunction and oxidative stress in both human and animal cells. However, the mechanisms which hypoxia causes mitochondrial dysfunction and energy metabolism misbalance still remain unclear. In this study, we presented evidence that mitochondrial phosphatase Ptpmt1 is a hypoxia response molecule that regulates cell proliferation, survival and glucose metabolism in human erythroleukemia TF-1 cells. Exposure to hypoxia or DFO treatment results in upregulation of HIF1-α, HIF-2α and Ptpmt1. Only inhibition of HIF-2α by shRNA transduction reduces Ptpmt1 expression in TF-1 cells under hypoxia. Ptpmt1 inhibitor suppresses the growth and induces apoptosis of TF-1 cells. Furthermore, we demonstrated that Ptpmt1 inhibition reduces the Glut1 and Glut3 expression and decreases the glucose consumption in TF-1 cells. In additional, Ptpmt1 knockdown also results in the mitochondrial dysfunction determined by JC1 staining. These results delineate a key role for HIF-2α-induced Ptpmt1 upregulation in proliferation, survival and glucose metabolism of erythroleukemia cells. It is indicated that Ptpmt1 plays important roles in hypoxia-induced cell metabolism and mitochondrial dysfunction.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Glucosa/metabolismo , Leucemia Eritroblástica Aguda/metabolismo , Fosfohidrolasa PTEN/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Hipoxia de la Célula , Línea Celular Tumoral , Proliferación Celular , Regulación hacia Abajo/genética , Transportador de Glucosa de Tipo 1/genética , Transportador de Glucosa de Tipo 1/metabolismo , Transportador de Glucosa de Tipo 3/genética , Transportador de Glucosa de Tipo 3/metabolismo , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Leucemia Eritroblástica Aguda/patología , Fosfohidrolasa PTEN/genética
11.
Tumour Biol ; 37(10): 13333-13343, 2016 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-27460081

RESUMEN

Liposarcoma(LPS) is the most common type of soft tissue sarcoma accounting for 20 % of all adult sarcomas. However, the molecular pathogenesis of this malignancy is still poorly understood. Here, we showed that GPS2 expression was downregulated in LPS and correlated with the prognosis of this disease. In vitro study showed that knockdown of GPS2 resulted in enhanced proliferation and migration of LPS cell line SW872, without significant influence of cell death. Conclusively, our results suggest that GPS2 may act as a tumor suppressor in LPS and serve as a potential prognosis marker for this disease.


Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/metabolismo , Liposarcoma/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Adipogénesis , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis/genética , Biomarcadores , Ciclo Celular/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular , Femenino , Estudios de Seguimiento , Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Inmunohistoquímica , Péptidos y Proteínas de Señalización Intracelular/genética , Liposarcoma/genética , Liposarcoma/mortalidad , Liposarcoma/patología , Masculino , Persona de Mediana Edad , Pronóstico , Transducción de Señal , Proteínas Supresoras de Tumor/genética
12.
Cytotherapy ; 18(3): 402-12, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26857230

RESUMEN

BACKGROUND AIMS: Specific and effective therapy for prevention or reversal of bronchiolitis obliterans (BO) is lacking. In this study, we evaluated the therapeutic effect of hepatocyte growth factor (HGF) gene modified mesenchymal stromal cells (MSCs) on BO. METHODS: A mouse model of experimental BO was established by subcutaneously transplanting the tracheas from C57BL/6 mice into Balb/C recipients, which were then administered saline, Ad-HGF-modified human umbilical cord-MSCs (MSCs-HGF) or Ad-Null-modified MSCs (MSCs-Null). The therapeutic effects of MSCs-Null and MSCs-HGF were evaluated by using fluorescence-activated cell sorting (FACS) for lymphocyte immunophenotype of spleen, enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (rt-PCR) for cytokine expression, and histopathological analysis for the transplanted trachea. RESULTS: The histopathologic recovery of allograft tracheas was improved significantly after MSCs-Null and MSCs-HGF treatment and the beneficial effects were particularly observed in MSCs-HGF-treated mice. Furthermore, the allo-transplantation-induced immunophenotype disorders of the spleen, including regulatory T (Treg), T helper (Th)1, Th2 and Th17, were attenuated in both cell-treated groups. MSCs-HGF treatment reduced expression and secretion of inflammation cytokines interferon-gamma (IFN-γ), and increased expression of anti-inflammatory cytokine interleukin (IL)-4 and IL-10. It also decreased the expression level of the profibrosis factor transforming growth factor (TGF)-ß. CONCLUSION: Treatment of BO with HGF gene modified MSCs results in reduction of local inflammation and promotion in recovery of allograft trachea histopathology. These findings might provide an effective therapeutic strategy for BO.


Asunto(s)
Bronquiolitis Obliterante/terapia , Terapia Genética/métodos , Factor de Crecimiento de Hepatocito/genética , Inflamación/prevención & control , Trasplante de Células Madre Mesenquimatosas , Cordón Umbilical/citología , Animales , Bronquiolitis Obliterante/genética , Bronquiolitis Obliterante/patología , Células Cultivadas , Modelos Animales de Enfermedad , Femenino , Factor de Crecimiento de Hepatocito/metabolismo , Humanos , Inmunomodulación/genética , Inflamación/genética , Inflamación/patología , Masculino , Células Madre Mesenquimatosas/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Linfocitos T Reguladores/inmunología
13.
Biochem Biophys Res Commun ; 460(2): 409-15, 2015 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-25791478

RESUMEN

SUMO/sentrin specific protease 1 (Senp1) is an important regulation protease in the protein sumoylation, which affects the cell cycle, proliferation and differentiation. The role of Senp1 mediated protein desumoylation in pathophysiological progression of multiple myeloma is unknown. In this study, we demonstrated that Senp1 is overexpressed and induced by IL-6 in multiple myeloma cells. Lentivirus-mediated Senp1 knockdown triggers apoptosis and reduces viability, proliferation and colony forming ability of MM cells. The NF-κB family members including P65 and inhibitor protein IkBα play important roles in regulation of MM cell survival and proliferation. We further demonstrated that Senp1 inhibition decreased IL-6-induced P65 and IkBα phosphorylation, leading to inactivation of NF-кB signaling in MM cells. These results delineate a key role for Senp1in IL-6 induced proliferation and survival of MM cells, suggesting it may be a potential new therapeutic target in MM.


Asunto(s)
Apoptosis , División Celular , Endopeptidasas/metabolismo , Mieloma Múltiple/patología , FN-kappa B/metabolismo , Transducción de Señal , Línea Celular Tumoral , Cisteína Endopeptidasas , Endopeptidasas/genética , Técnicas de Silenciamiento del Gen , Silenciador del Gen , Células HEK293 , Humanos , Mieloma Múltiple/metabolismo
14.
J Cancer Res Clin Oncol ; 150(1): 8, 2024 Jan 09.
Artículo en Inglés | MEDLINE | ID: mdl-38195952

RESUMEN

BACKGROUND: NUDT21 (Nudix Hydrolase 21) has been shown to play an essential role in multiple biological processes. Pancreatic adenocarcinoma (PAAD) is one of the most fatal cancers in the world. However, the biological function of NUDT21 in PAAD remains rarely understood. The aim of this research was to identify the prediction value of NUDT21 in diagnosis, prognosis, immune infiltration, and signal pathway in PAAD. METHODS: Combined with the data in online databases, we analyzed the expression, immune infiltration, function enrichment, signal pathway, diagnosis, and prognosis of NUDT21 in PAAD. Then, the biological function of NUDT21 and its interacted protein in PAAD was identified through plasmid transduction system and protein mass spectrometry. Expression of NUDT21 was further verified in clinical specimens by immunofluorescence. RESULTS: We found that NUDT21 was upregulated in PAAD tissues and was significantly associated with the diagnosis and prognosis of pancreatic cancer through bioinformatic data analysis. We also found that overexpression of NUDT21 enhanced PAAD cells proliferation and migration, whereas knockdown NUDT21 restored the effects through in vitro experiment. Moreover, NDUFS2 was recognized as a potential target of NUDT21.We further verified that the expression of NDUFS2 was positively correlated with NUDT21 in PAAD clinical specimens. Mechanically, we found that NUDT21 stabilizes NDUFS2 and activates the PI3K-AKT signaling pathway. CONCLUSION: Our investigation reveals that NUDT21 is a previously unrecognized oncogenic factor in the diagnosis, prognosis, and treatment target of PAAD, and we suggest that NUDT21 might be a novel therapeutic target in PAAD.


Asunto(s)
Adenocarcinoma , Factor de Especificidad de Desdoblamiento y Poliadenilación , NADH Deshidrogenasa , Neoplasias Pancreáticas , Humanos , Adenocarcinoma/genética , Proliferación Celular , NADH Deshidrogenasa/genética , Neoplasias Pancreáticas/genética , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Factor de Especificidad de Desdoblamiento y Poliadenilación/genética
15.
Cell Death Discov ; 10(1): 190, 2024 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-38653740

RESUMEN

Pancreatic cancer is one of the most fatal cancers in the world. A growing number of studies have begun to demonstrate that mitochondria play a key role in tumorigenesis. Our previous study reveals that NDUFS2 (NADH: ubiquinone oxidoreductase core subunit S2), a core subunit of the mitochondrial respiratory chain complex I, is upregulated in Pancreatic adenocarcinoma (PAAD). However, its role in the development of PAAD remains unknown. Here, we showed that NDUFS2 played a critical role in the survival, proliferation and migration of pancreatic cancer cells by inhibiting mitochondrial cell death. Additionally, protein mass spectrometry indicated that the NDUFS2 was interacted with a deubiquitinase, OTUB1. Overexpression of OTUB1 increased NDUFS2 expression at the protein level, while knockdown of OTUB1 restored the effects in vitro. Accordingly, overexpression and knockdown of OTUB1 phenocopied those of NDUFS2 in pancreatic cancer cells, respectively. Mechanically, NDUFS2 was deubiquitinated by OTUB1 via K48-linked polyubiquitin chains, resulted in an elevated protein stability of NDUFS2. Moreover, the growth of OTUB1-overexpressed pancreatic cancer xenograft tumor was promoted in vivo, while the OTUB1-silenced pancreatic cancer xenograft tumor was inhibited in vivo. In conclusion, we revealed that OTUB1 increased the stability of NDUFS2 in PAAD by deubiquitylation and this axis plays a pivotal role in pancreatic cancer tumorigenesis and development.

16.
Zhonghua Jie He He Hu Xi Za Zhi ; 36(11): 808-13, 2013 Nov.
Artículo en Zh | MEDLINE | ID: mdl-24507390

RESUMEN

OBJECTIVE: To study the efficacy of umbilical cord-derived mesenchymal stem cells (UC-MSCs) for bleomycin-induced pulmonary fibrosis in mice. METHODS: UC-MSCs were isolated from the umbilical cord after parental consent. One hundred C57BL/6 mice were randomly divided into 4 groups (12 of these for preliminary experiment). Mice in the control group (n = 20) were instilled with PBS via trachea and NS was injected via the tail vein after 3 days. Mice in the stem cell group (n = 20) were instilled with PBS via trachea and were injected with MSC via the tail vein after 3 days. Mice in the bleomycin group (n = 24) were instilled with bleomycin via trachea and NS was injected via the tail vein after 3 days. Mice in the bleomycin plus stem cell group (n = 24) were instilled with bleomycin via trachea and were injected with MSCs via the tail vein after 3 days. All of the mice were sacrificed at the 21(th) day, and the lungs were immediately fixed with 4% paraformaldehyde for 48 h, embedded in paraffin and sectioned at 5 µmol/L thickness. The sections were stained with hematoxylin and eosin (H&E) and Masson-trichrome. Histopathological scoring of pulmonary fibrosis was performed according to Ashcroft's method. The concentrations of matrix metalloproteinases-2 and tissue inhibitor of metalloproteinase-1were determined using immunohistochemistry. RESULTS: Compared with the bleomycin group, MSC transplantation significantly reduced pulmonary inflammation, fibrosis and deposition of collagen in the bleomycin plus stem cell group [(1.55 ± 0.51) vs (2.16 ± 0.77), and (1.45 ± 0.60) vs (2.32 ± 0.82), respectively, P < 0.05]. There was no difference between the control group and the stem cell group [(0.35 ± 0.49) vs (0.37 ± 0.50), P > 0.05]. The expression of MMP-2 in the bleomycin plus stem cell group was lower than the bleomycin group [(1.59 ± 0.59) vs (2.37 ± 0.68), P < 0.05], but there was no difference between the control group and the stem cell group [(0.80 ± 0.69) vs (0.84 ± 0.77), P > 0.05]. The expression of TIMP-1 in the bleomycin plus stem cell group was higher than the bleomycin group [(1.95 ± 0.58) vs (0.79 ± 0.71), P < 0.05], but there was no difference between the control group and the stem cell group [(1.10 ± 0.72) vs (1.32 ± 0.58), P > 0.05]. CONCLUSION: UC-MSC transplantation could relieve bleomycin-induced fibrosing alveolitis in mice. The mechanism might be related to the expression of MMP-2 and TIMP-1. UC-MSC had no effect on normal lungs.


Asunto(s)
Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/citología , Fibrosis Pulmonar/terapia , Cordón Umbilical/citología , Animales , Bleomicina/efectos adversos , Células Cultivadas , Modelos Animales de Enfermedad , Citometría de Flujo , Humanos , Inmunohistoquímica , Pulmón/metabolismo , Pulmón/patología , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/metabolismo , Distribución Aleatoria , Inhibidor Tisular de Metaloproteinasa-1/metabolismo
17.
Am J Cancer Res ; 13(3): 992-1003, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37034225

RESUMEN

Pancreatic ductal adenocarcinoma is a highly malignant cancer with poor prognosis, for which effective therapeutic strategies are urgently needed. The dual-specificity phosphatase PTPMT1 is localized in mitochondria and highly expressed in various cancers. Here, we investigated the function of PTPMT1 in pancreatic ductal adenocarcinoma. We inhibited its expression in pancreatic cancer cell lines using siRNAs or the specific PTPMT1 inhibitor alexidine dihydrochloride and observed that PTPMT1 silencing in pancreatic cancer cell lines drastically reduced cell viability, caused mitochondrial damage, and impaired mitochondrial function. Co-immunoprecipitation analysis demonstrated that PTPMT1 could interact with SLC25A6 and NDUFS2, indicating that it may modulate mitochondrial function via the SLC25A6-NDUFS2 axis. Collecively, our data highlight PTPMT1 as an important factor in pancreatic ductal adenocarcinoma and a potential therapeutic target.

18.
J Inflamm Res ; 16: 2023-2039, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37197438

RESUMEN

Purpose: Mesenchymal stem cells (MSCs) have become novel therapeutic agents for the treatment of inflammatory bowel diseases (IBDs). However, the precise cellular and molecular mechanisms by which MSCs restore intestinal tissue homeostasis and repair the epithelial barrier have not been well elucidated. This study aimed to investigate the therapeutic effects and possible mechanisms of human MSCs in the treatment of experimental colitis. Methods: We performed an integrative transcriptomic, proteomic, untargeted metabolomics, and gut microbiota analyses in a dextran sulfate sodium (DSS)-induced IBD mouse model. The cell viability of IEC-6 cells was determined by Cell Counting Kit-8 (CCK-8) assay. The expression of MUC-1 and ferroptosis-related genes were determined by immunohistochemical staining, Western blot, and real-time quantitative polymerase chain reaction (RT-qPCR). Results: Mice treated with MSCs showed notable amelioration in the severity of DSS-induced colitis, which was associated with reduced levels of proinflammatory cytokines and restoration of the lymphocyte subpopulation balance. Treatment with MSC restored the gut microbiota and altered their metabolites in DSS-induced IBD mice. The 16s rDNA sequencing showed that treatment with MSC modulated the composition of probiotics, including the upregulation of the contents of Firmicutes, Lactobacillus, Blautia, Clostridia, and Helicobacter bacteria in mouse colons. Protein proteomics and transcriptome analyses revealed that pathways related to cell immune responses, including inflammatory cytokines, were suppressed in the MSC group. The ferroptosis-related gene, MUC-1, was significantly upregulated in the MSC-treated group. MUC-1-inhibition experiments indicated that MUC-1 was essential for epithelial cell growth. Through overexpression of MUC-1, it showed that upregulation of SLC7A11 and GPX4, and downregulation of ACSL4 in erastin and RSL3-treated IEC-6 cells, respectively. Conclusion: This study described a mechanism by which treatment with MSCs ameliorated the severity of DSS-induced colitis by modulating the gut microbiota, immune response, and the MUC-1 pathway.

19.
Anticancer Drugs ; 23(1): 22-31, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21857502

RESUMEN

Lipid rafts mediate several survival signals in the development of chronic myeloid leukemia (CML). Methyl-ß-cyclodextrin (MßCD) is an inhibitor specifically designed to disrupt lipid rafts in cells by depleting the cholesterol component. We hypothesize that treatment of CML cells with MßCD and imatinib could reduce imatinib resistance. Apoptotic and autophagic cell death was assayed using annexin V-propidium iodide double staining, immunoblotting, and immunocytochemistry. We next investigated whether MßCD could enhance the cytotoxicity of imatinib in imatinib-sensitive and imatinib-resistant K562 cells. Extracellular signal-regulated kinase/sphingosine kinase 1 signaling downstream of lipid raft-activated signaling pathways was significantly inhibited by treatment of cells with a combination of MßCD and imatinib compared with treatment with either agent alone. MßCD induces programmed cell death in CML cells, and its antileukemia action is synergistic with that of imatinib.


Asunto(s)
Antineoplásicos/farmacología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Piperazinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , beta-Ciclodextrinas/farmacología , Apoptosis/efectos de los fármacos , Benzamidas , Caspasa 3/metabolismo , Línea Celular Tumoral , Regulación hacia Abajo/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Sinergismo Farmacológico , Humanos , Mesilato de Imatinib , Células K562 , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Microdominios de Membrana/metabolismo , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética
20.
Asian J Surg ; 45(11): 2214-2223, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-35000852

RESUMEN

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a fatal malignancy due to the lack of early detection method, therapeutic drug and target. We noticed that the expression of Protein Tyrosine Phosphatase Mitochondria1(PTPMT1) is upregulated in PDAC. However, its role in pancreatic cancer remains unknown. METHODS: We first analyzed the expression of PTPMT1 from 50 PDAC patients. Secondly, the survival proportions of different PTPMT1-expressed patients were analyzed. Then, the role and mechanism of PTPMT1 in PDAC were studied by lentivirus transduction system. RESULTS: PTPMT1 was upregulated in PDAC and patients with high PTPMT1 expression displayed lower overall survival rate. Knockdown of PTPMT1 increased the sensitivity to erastin or RSL3 induced ferroptosis. Mechanically, knockdown of PTPMT1 resulted in upregulated Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4) and downregulated Solute Carrier Family 7 Member 11 (SLC7A11). In addition, SLC7A11 was upregulated in PDAC tumor tissue and correlated positively with the expression of PTPMT1. However, the expression of ACSL4 was downregulated in PDAC and negatively correlated with the expression of PTPMT1. CONCLUSION: Our study demonstrates that PTPMT1 is upregulated in PDAC and PTPMT1 inhibits ferroptosis by suppressing the expression of ACSL4 and upregulating SLC7A11 in Panc-1 cells, suggesting PTPMT1 might be a potential prognosis biomarker and therapeutic target in PDAC.


Asunto(s)
Carcinoma Ductal Pancreático , Ferroptosis , Neoplasias Pancreáticas , Biomarcadores , Carcinoma Ductal Pancreático/genética , Coenzima A , Ferroptosis/genética , Humanos , Ligasas , Fosfohidrolasa PTEN , Neoplasias Pancreáticas/genética , Piperazinas , Proteínas Tirosina Fosfatasas , Neoplasias Pancreáticas
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