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1.
Stem Cells Dev ; 33(3-4): 89-103, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38164089

RESUMEN

Mesenchymal stem cells (MSCs) directly differentiate into neurons and endothelial cells after transplantation, and their secretome has considerable potential for treating brain injuries. Previous studies have suggested that the effects of MSCs priming with exposure to hypoxia, cytokines, growth factors, or chemical agents could optimize the paracrine potency and therapeutic potential of MSCs. Studies have suggested that thrombin-primed Wharton's Jelly-derived mesenchymal stem cells (Th.WJ-MSCs) significantly enhance the neuroprotective beneficial effects of naive MSCs in brain injury such as hypoxic-ischemic brain injury (HIE) and intraventricular hemorrhage (IVH). This study aimed to characterize WJ-MSCs in terms of stem cell markers, differentiation, cell proliferation, and paracrine factors by comparing naive and Th.WJ-MSCs. We demonstrated that compared with naive MSCs, Th.MSCs significantly enhanced the neuroprotective effects in vitro. Moreover, we identified differentially expressed proteins in the conditioned media of naive and Th.WJ-MSCs by liquid chromatography-tandem mass spectrometry analysis. Secretome analysis of the conditioned medium of WJ-MSCs revealed that such neuroprotective effects were mediated by paracrine effects with secretomes of Th.WJ-MSCs, and hepatocyte growth factor was identified as a key paracrine mediator. These results can be applied further in the preclinical and clinical development of effective and safe cell therapeutics for brain injuries such as HIE and IVH.


Asunto(s)
Lesiones Encefálicas , Células Madre Mesenquimatosas , Fármacos Neuroprotectores , Factor de Transcripción STAT3 , Gelatina de Wharton , Humanos , Factor de Crecimiento de Hepatocito/metabolismo , Fármacos Neuroprotectores/farmacología , Trombina/farmacología , Trombina/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Células Endoteliales/metabolismo , Células Cultivadas , Transducción de Señal , Diferenciación Celular , Factores Inmunológicos/metabolismo , Lesiones Encefálicas/metabolismo , Proliferación Celular
2.
Aging (Albany NY) ; 14(22): 8944-8969, 2022 11 29.
Artículo en Inglés | MEDLINE | ID: mdl-36446389

RESUMEN

Mismatches between pre-clinical and clinical results of stem cell therapeutics for ischemic stroke limit their clinical applicability. To overcome these discrepancies, precise planning of pre-clinical experiments that can be translated to clinical trials and the scientific elucidation of treatment mechanisms is important. In this study, adult human neural stem cells (ahNSCs) derived from temporal lobe surgical samples were used (to avoid ethical and safety issues), and their therapeutic effects on ischemic stroke were examined using middle cerebral artery occlusion animal models. 5 × 105 ahNSCs was directly injected into the lateral ventricle of contralateral brain hemispheres of immune suppressed rat stroke models at the subacute phase of stroke. Compared with the mock-treated group, ahNSCs reduced brain tissue atrophy and neurological sensorimotor and memory functional loss. Tissue analysis demonstrated that the significant therapeutic effects were mediated by the neuroprotective and pro-angiogenic activities of ahNSCs, which preserved neurons in ischemic brain areas and decreased reactive astrogliosis and microglial activation. The neuroprotective and pro-angiogenic effects of ahNSCs were validated in in vitro stroke models and were induced by paracrine factors excreted by ahNSCs. When the JAK2/STAT3 signaling pathway was inhibited by a specific inhibitor, AG490, the paracrine neuroprotective and pro-angiogenic effects of ahNSCs were reversed. This pre-clinical study that closely simulated clinical settings and provided treatment mechanisms of ahNSCs for ischemic stroke may aid the development of protocols for subsequent clinical trials of ahNSCs and the realization of clinically available stem cell therapeutics for ischemic stroke.


Asunto(s)
Accidente Cerebrovascular Isquémico , Células-Madre Neurales , Fármacos Neuroprotectores , Accidente Cerebrovascular , Animales , Humanos , Ratas , Inductores de la Angiogénesis , Modelos Animales de Enfermedad , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/terapia , Janus Quinasa 2/metabolismo , Modelos Animales , Células-Madre Neurales/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Factor de Transcripción STAT3/metabolismo , Accidente Cerebrovascular/tratamiento farmacológico
3.
BMB Rep ; 55(10): 512-517, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-36104258

RESUMEN

Traumatic brain injury (TBI) is brain damage which is caused by the impact of external mechanical forces. TBI can lead to the temporary or permanent impairment of physical and cognitive abilities, resulting in abnormal behavior. We recently observed that a single session of early exercise in animals with TBI improved their behavioral performance in the absence of other cognitive abnormalities. In the present study, we investigated the therapeutic effects of continuous exercise during the early stages of TBI in rats. We found that continuous low-intensity exercise in early-stage improves the locomotion recovery in the TBI of animal models; however, it does not significantly enhance short-term memory capabilities. Moreover, continuous early exercise not only reduces the protein expression of cerebral damage-related markers, such as Glial Fibrillary Acid Protein (GFAP), Neuron-Specific Enolase (NSE), S100ß, Protein Gene Products 9.5 (PGP9.5), and Heat Shock Protein 70 (HSP70), but it also decreases the expression of apoptosis-related protein BAX and cleaved caspase 3. Furthermore, exercise training in animals with TBI decreases the microglia activation and the expression of inflammatory cytokines in the serum, such as CCL20, IL-13, IL-1α, and IL-1ß. These findings thus demonstrate that early exercise therapy for TBI may be an effective strategy in improving physiological function, and that serum protein levels are useful biomarkers for the predicition of the effectiveness of early exercise therapy.[BMB Reports 2022; 55(10): 506-511].


Asunto(s)
Lesiones Traumáticas del Encéfalo , Ratas , Animales , Lesiones Traumáticas del Encéfalo/terapia , Lesiones Traumáticas del Encéfalo/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismo , Biomarcadores , Citocinas/metabolismo , Encéfalo/metabolismo , Modelos Animales de Enfermedad
4.
Int J Mol Sci ; 23(8)2022 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-35457084

RESUMEN

The limited capability of regeneration in the human central nervous system leads to severe and permanent disabilities following spinal cord injury (SCI) while patients suffer from no viable treatment option. Adult human neural stem cells (ahNSCs) are unique cells derived from the adult human brain, which have the essential characteristics of NSCs. The objective of this study was to characterize the therapeutic effects of ahNSCs isolated from the temporal lobes of focal cortical dysplasia type IIIa for SCI and to elucidate their treatment mechanisms. Results showed that the recovery of motor functions was significantly improved in groups transplanted with ahNSCs, where, in damaged regions of spinal cords, the numbers of both spread and regenerated nerve fibers were observed to be higher than the vehicle group. In addition, the distance between neuronal nuclei in damaged spinal cord tissue was significantly closer in treatment groups than the vehicle group. Based on an immunohistochemistry analysis, those neuroprotective effects of ahNSCs in SCI were found to be mediated by inhibiting apoptosis of spinal cord neurons. Moreover, the analysis of the conditioned medium (CM) of ahNSCs revealed that such neuroprotective effects were mediated by paracrine effects with various types of cytokines released from ahNSCs, where monocyte chemoattractant protein-1 (MCP-1, also known as CCL2) was identified as a key paracrine mediator. These results of ahNSCs could be utilized further in the preclinical and clinical development of effective and safe cell therapeutics for SCI, with no available therapeutic options at present.


Asunto(s)
Células-Madre Neurales , Fármacos Neuroprotectores , Traumatismos de la Médula Espinal , Adulto , Quimiocina CCL2 , Humanos , Células-Madre Neurales/trasplante , Fármacos Neuroprotectores/uso terapéutico , Recuperación de la Función/fisiología , Médula Espinal , Traumatismos de la Médula Espinal/tratamiento farmacológico
5.
BMB Rep ; 55(7): 336-341, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-35168701

RESUMEN

Narrowing of arteries supplying blood to the limbs provokes critical hindlimb ischemia (CLI). Although CLI results in irreversible sequelae, such as amputation, few therapeutic options induce the formation of new functional blood vessels. Based on the proangiogenic potentials of stem cells, in this study, it was examined whether a combination of dental pulp stem cells (DPSCs) and human umbilical vein endothelial cells (HUVECs) could result in enhanced therapeutic effects of stem cells for CLI compared with those of DPSCs or HUVECs alone. The DPSCs+ HUVECs combination therapy resulted in significantly higher blood flow and lower ischemia damage than DPSCs or HUVECs alone. The improved therapeutic effects in the DPSCs+ HUVECs group were accompanied by a significantly higher number of microvessels in the ischemic tissue than in the other groups. In vitro proliferation and tube formation assay showed that VEGF in the conditioned media of DPSCs induced proliferation and vessel-like tube formation of HUVECs. Altogether, our results demonstrated that the combination of DPSCs and HUVECs had significantly better therapeutic effects on CLI via VEGF-mediated crosstalk. This combinational strategy could be used to develop novel clinical protocols for CLI proangiogenic regenerative treatments. [BMB Reports 2022; 55(7): 336-341].


Asunto(s)
Neovascularización Fisiológica , Factor A de Crecimiento Endotelial Vascular , Animales , Diferenciación Celular , Proliferación Celular , Células Cultivadas , Pulpa Dental , Miembro Posterior/irrigación sanguínea , Células Endoteliales de la Vena Umbilical Humana , Humanos , Isquemia/terapia , Trasplante de Células Madre
6.
Stem Cells Int ; 2021: 6737288, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34434240

RESUMEN

Adult human multipotent neural cells (ahMNCs) are unique cells derived from adult human temporal lobes. They show multipotent differentiation potentials into neurons and astrocytes. In addition, they possess proangiogenic capacities. The objective of this study was to characterize ahMNCs in terms of expression of cell type-specific markers, in vitro differentiation potentials, and paracrine factors compared with several other cell types including fetal neural stem cells (fNSCs) to provide detailed molecular and functional features of ahMNCs. Interestingly, the expression of cell type-specific markers of ahMNCs could not be differentiated from those of pericytes, mesenchymal stem cells (MSCs), or fNSCs. In contrast, differentiation potentials of ahMNCs and fNSCs into neural cells were higher than those of other cell types. Compared with MSCs, ahMNCs showed lower differentiation capacities into osteogenic and adipogenic cells. Moreover, ahMNCs uniquely expressed higher levels of MCP-1 and GRO family paracrine factors than fNSCs and MSCs. These high levels of MCP-1 and GRO family mediated in vivo proangiogenic effects of ahMNCs. These results indicate that ahMNCs have their own distinct characteristics that could distinguish ahMNCs from other cell types. Characteristics of ahMNCs could be utilized further in the preclinical and clinical development of ahMNCs for regenerative medicine. They could also be used as experimental references for other cell types including fNSCs.

7.
Anticancer Res ; 41(7): 3349-3361, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-34230131

RESUMEN

BACKGROUND/AIM: The present study investigated the oncogenic functions of TACC3 in the progression of gastric cancer (GC). MATERIALS AND METHODS: We analysed TACC3 in relation to cell growth, invasion capability, expression of epithelial-mesenchymal transition (EMT)-related markers, and ERK/Akt/cyclin D1 signaling factors. The correlation between the immunohistochemically confirmed expression of TACC3 and clinical factors was also analyzed. RESULTS: The increased proliferation and invasion of TACC3-over-expressing GC cells was accompanied by altered regulation of EMT-associated markers and activation of ERK/Akt/cyclin D1 signaling. Immunohistochemical analysis of TACC3 in human GC tissues revealed that its expression is correlated with aggressive characteristics and poor prognosis of intestinal-type GC. CONCLUSION: TACC3 contributes to gastric tumorigenesis by promoting EMT via the ERK/Akt/cyclin D1 signaling pathway. The correlation between TACC3 expression and multiple clinicopathological variables implies that its effective therapeutic targeting in GC will depend on the tumor subtype.


Asunto(s)
Carcinogénesis/genética , Ciclina D1/genética , Transición Epitelial-Mesenquimal/genética , Sistema de Señalización de MAP Quinasas/genética , Proteínas Asociadas a Microtúbulos/genética , Proteínas Proto-Oncogénicas c-akt/genética , Neoplasias Gástricas/genética , Carcinogénesis/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Transducción de Señal/genética , Estómago/patología , Neoplasias Gástricas/patología
8.
Int J Mol Sci ; 22(5)2021 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-33806636

RESUMEN

Stem cell-based therapeutics are amongst the most promising next-generation therapeutic approaches for the treatment of spinal cord injury (SCI), as they may promote the repair or regeneration of damaged spinal cord tissues. However, preclinical optimization should be performed before clinical application to guarantee safety and therapeutic effect. Here, we investigated the optimal injection route and dose for adult human multipotent neural cells (ahMNCs) from patients with hemorrhagic stroke using an SCI animal model. ahMNCs demonstrate several characteristics associated with neural stem cells (NSCs), including the expression of NSC-specific markers, self-renewal, and multi neural cell lineage differentiation potential. When ahMNCs were transplanted into the lateral ventricle of the SCI animal model, they specifically migrated within 24 h of injection to the damaged spinal cord, where they survived for at least 5 weeks after injection. Although ahMNC transplantation promoted significant locomotor recovery, the injection dose was shown to influence treatment outcomes, with a 1 × 106 (medium) dose of ahMNCs producing significantly better functional recovery than a 3 × 105 (low) dose. There was no significant gain in effect with the 3 × 106 ahMNCs dose. Histological analysis suggested that ahMNCs exert their effects by modulating glial scar formation, neuroprotection, and/or angiogenesis. These data indicate that ahMNCs from patients with hemorrhagic stroke could be used to develop stem cell therapies for SCI and that the indirect injection route could be clinically relevant. Moreover, the optimal transplantation dose of ahMNCs defined in this preclinical study might be helpful in calculating its optimal injection dose for patients with SCI in the future.


Asunto(s)
Células Madre Multipotentes/patología , Células-Madre Neurales/patología , Traumatismos de la Médula Espinal/patología , Médula Espinal/patología , Adulto , Animales , Diferenciación Celular/fisiología , Células Cultivadas , Femenino , Humanos , Ratas , Ratas Sprague-Dawley , Recuperación de la Función/fisiología , Trasplante de Células Madre/métodos
9.
BMB Rep ; 53(10): 539-544, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-32843132

RESUMEN

Skin aging appears to be the result of overlapping intrinsic (including genetic and hormonal factors) and extrinsic (external environment including chronic light exposure, chemicals, and toxins) processes. These factors cause decreases in the synthesis of collagen type I and elastin in fibroblasts and increases in the melanin in melanocytes. Collagen Type I is the most abundant type of collagen and is a major structural protein in human body tissues. In previous studies, many products containing collagen derived from land and marine animals as well as other sources have been used for a wide range of purposes in cosmetics and food. However, to our knowledge, the effects of human collagenderived peptides on improvements in skin condition have not been investigated. Here we isolate and identify the domain of a human COL1A2-derived protein which promotes fibroblast cell proliferation and collagen type I synthesis. This human COL 1A2-derived peptide enhances wound healing and elastin production. Finally, the human collagen alpha-2 type I-derived peptide (SMM) ameliorates collagen type I synthesis, cell proliferation, cell migration, and elastin synthesis, supporting a significant anti-wrinkle effect. Collectively, these results demonstrate that human collagen alpha-2 type I-derived peptides is practically accessible in both cosmetics and food, with the goal of improving skin condition. [BMB Reports 2020; 53(10): 539-544].


Asunto(s)
Colágeno Tipo I/metabolismo , Fibroblastos/metabolismo , Piel/metabolismo , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Colágeno/biosíntesis , Colágeno/metabolismo , Colágeno Tipo I/fisiología , Elastina/biosíntesis , Elastina/metabolismo , Elastina/farmacología , Humanos , Envejecimiento de la Piel/fisiología , Cicatrización de Heridas/fisiología
10.
Anticancer Res ; 40(2): 723-731, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32014914

RESUMEN

BACKGROUND/AIM: MicroRNAs (miRNAs) play regulatory roles in pancreatic ductal adenocarcinoma (PDAC). However, it is still required to identify the function of miRNA-301-3p in pancreatic cancer cells. MATERIALS AND METHODS: Effects of luteolin on cell growth, TRAIL cytotoxicity, and miR-301-3p levels were evaluated. The role of miRNA-301-3p in regulating cell proliferation, target gene expression, and TRAIL cytotoxicity were studied. RESULTS: The levels of miR-301-3p were down-regulated in PANC-1 cells exposed to luteolin, which inhibits the growth of PANC-1 cells and sensitizes cells to TRAIL. The knockdown of miR-301-3p attenuates cell proliferation and enhances TRAIL cytotoxicity. In addition, caspase-8 was directly targeted by miR-301-3p. CONCLUSION: Our findings unveil a critical biological function of miR-301-3p in regulating cell proliferation and elevating an antiproliferative effect of TRAIL on cancer cells. Our observation of miR-301-3p/caspase-8 relationship can also serve to clarify the role of miR-301-3p in other cancer types and related diseases.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Caspasa 8/metabolismo , Luteolina/farmacología , MicroARNs/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Carcinoma Ductal Pancreático/genética , Caspasa 8/genética , Línea Celular Tumoral , Regulación hacia Abajo/efectos de los fármacos , Sinergismo Farmacológico , Técnicas de Silenciamiento del Gen , Humanos , Luteolina/administración & dosificación , MicroARNs/genética , Neoplasias Pancreáticas/genética , Proteínas Recombinantes/farmacología , Ligando Inductor de Apoptosis Relacionado con TNF/administración & dosificación , Transfección
11.
J Biol Chem ; 294(42): 15435-15445, 2019 10 18.
Artículo en Inglés | MEDLINE | ID: mdl-31471318

RESUMEN

Akt signaling is an important regulator of neural development, but the distinctive function of Akt isoforms in brain development presents a challenge. Here we show Siah1 as an ubiquitin ligase that preferentially interacts with Akt3 and facilitates ubiquitination and degradation of Akt3. Akt3 is enriched in the axonal shaft and branches but not growth cone tips, where Siah1 is prominently present. Depletion of Siah1 enhanced Akt3 levels in the soma and axonal tips, eliciting multiple branching. Brain-specific somatic mutation in Akt3-E17K escapes from Siah1-mediated degradation and causes improper neural development with dysmorphic neurons. Remarkably, coexpression of Siah1 with Akt3-WT restricted disorganization of neural development is caused by Akt3 overexpression, whereas forced expression of Siah1 with the Akt3-E17K mutant fails to cope with malformation of neural development. These findings demonstrate that Siah1 limits Akt3 turnover during brain development and that this event is essential for normal organization of the neural network.


Asunto(s)
Encéfalo/crecimiento & desarrollo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Axones/metabolismo , Encéfalo/metabolismo , Ratones , Neurogénesis , Neuronas/metabolismo , Proteolisis , Proteínas Proto-Oncogénicas c-akt/genética , Ratas , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitinación
12.
Oncogene ; 37(46): 6069-6082, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-29991800

RESUMEN

Autophagy is an evolutionarily conserved process regulating cellular homeostasis via digestion of dysfunctional proteins and whole cellular organelles by mechanisms, involving their enclosure into double-membrane vacuoles that are subsequently fused to lysosomes. Glioma stem cells utilize autophagy as a main mechanism of cell survival and stress response. Most recently, we and others demonstrated induction of autophagy in gliomas in response to treatment with chemical drugs, such as temozolomide (TMZ) or oncolytic adenoviruses (Ads). As autophagy has been implicated in the mechanism of Ad-mediated cell killing, autophagy deficiency in some glioma tumors could be the reason for their resistance to oncolysis. Despite the observed connection, the exact relationship between autophagy-activating cell signaling and adenoviral infection remains unclear. Here, we report that inhibition of autophagy in target glioma cells induces their resistance to killing by oncolytic agent CRAd-S-5/3. Furthermore, we found that downregulation of autophagy inducer Beclin-1 inhibits replication-competent Ad-induced oncolysis of human glioma by suppressing cell proliferation and inducing premature senescence. To overcome the autophagy-deficient state of such glioma cells and restore their susceptibility to oncolytic Ad infection, we propose treating glioma tumors with an anticancer drug tamoxifen (TAM) as a means to induce apoptosis in Ad-targeted cancer cells via upregulation of BAX/PUMA genes. In agreement with the above hypothesis, our data suggest that TAM improves susceptibility of Beclin-1-deficient glioma cells to CRAd-S-5/3 oncolysis by means of activating autophagy and pro-apoptotic signaling pathways in the target cancer cells.


Asunto(s)
Adenoviridae/genética , Proteínas Reguladoras de la Apoptosis/genética , Autofagia/efectos de los fármacos , Beclina-1/genética , Glioma/tratamiento farmacológico , Proteínas Proto-Oncogénicas/genética , Tamoxifeno/farmacología , Regulación hacia Arriba/genética , Proteína X Asociada a bcl-2/genética , Células A549 , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Autofagia/genética , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Línea Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Femenino , Glioma/genética , Células HEK293 , Humanos , Ratones , Viroterapia Oncolítica/métodos , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética
13.
Anticancer Res ; 38(3): 1303-1310, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29491053

RESUMEN

BACKGROUND/AIM: Breast cancer is the most common malignant cancer type in women, and triple-negative breast cancer (TNBC) is an extremely aggressive subtype of breast cancer with poor prognosis rates. The present study investigated the antitumor effect of polo-like kinase 1 (PLK1) inhibitor in combination with the tankyrase-1 (TNKS1) inhibitor on TNBC cells. MATERIALS AND METHODS: We evaluated the antitumor effects of combination therapy with PLK1 and TNKS1 inhibitor using cell viability analysis, apoptosis assay and transwell assay for cell invasion and migration in TNBC cells. RESULTS: Combination treatment with PLK1 and TNKS1 inhibitors not only inhibited the invasion and migration capacity of TNBC cells, but also increased the apoptosis and cell death of TNBC cells. The viability of TNBC cells with low expression of ß-catenin and high expression of PLK1 was not affected by treatment with PLK1 inhibitor. However, the combination treatment with the TNKS1 inhibitor significantly decreased cell invasion and migration and increased apoptosis. CONCLUSION: Combination therapy of PLK1 and TNKS1 inhibitors may improve the therapeutic efficacy of the current treatment for TNBC.


Asunto(s)
Proteínas de Ciclo Celular/antagonistas & inhibidores , Inhibidores Enzimáticos/uso terapéutico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Tanquirasas/antagonistas & inhibidores , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Apoptosis/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Sinergismo Farmacológico , Quimioterapia Combinada , Inhibidores Enzimáticos/farmacología , Femenino , Células HeLa , Humanos , Estimación de Kaplan-Meier , Células MCF-7 , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Interferencia de ARN , Tanquirasas/genética , Tanquirasas/metabolismo , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/metabolismo , Quinasa Tipo Polo 1
14.
Cancer Cell ; 32(6): 840-855.e8, 2017 Dec 11.
Artículo en Inglés | MEDLINE | ID: mdl-29232556

RESUMEN

ATG4B stimulates autophagy by promoting autophagosome formation through reversible modification of ATG8. We identify ATG4B as a substrate of mammalian sterile20-like kinase (STK) 26/MST4. MST4 phosphorylates ATG4B at serine residue 383, which stimulates ATG4B activity and increases autophagic flux. Inhibition of MST4 or ATG4B activities using genetic approaches or an inhibitor of ATG4B suppresses autophagy and the tumorigenicity of glioblastoma (GBM) cells. Furthermore, radiation induces MST4 expression, ATG4B phosphorylation, and autophagy. Inhibiting ATG4B in combination with radiotherapy in treating mice with intracranial GBM xenograft markedly slows tumor growth and provides a significant survival benefit. Our work describes an MST4-ATG4B signaling axis that influences GBM autophagy and malignancy, and whose therapeutic targeting enhances the anti-tumor effects of radiotherapy.


Asunto(s)
Proteínas Relacionadas con la Autofagia/metabolismo , Autofagia/fisiología , Neoplasias Encefálicas/patología , Cisteína Endopeptidasas/metabolismo , Glioblastoma/patología , Proteínas Serina-Treonina Quinasas/metabolismo , Animales , Neoplasias Encefálicas/metabolismo , Carcinogénesis/metabolismo , Línea Celular Tumoral , Glioblastoma/metabolismo , Humanos , Ratones , Ratones Desnudos , Fosforilación , Tolerancia a Radiación , Ensayos Antitumor por Modelo de Xenoinjerto
15.
Proc Natl Acad Sci U S A ; 114(31): 8366-8371, 2017 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-28716909

RESUMEN

CD44 has been postulated as a cell surface coreceptor for augmenting receptor tyrosine kinase (RTK) signaling. However, how exactly CD44 triggers RTK-dependent signaling remained largely unclear. Here we report an unexpected mechanism by which the CD44s splice isoform is internalized into endosomes to attenuate EGFR degradation. We identify a CD44s-interacting small GTPase, Rab7A, and show that CD44s inhibits Rab7A-mediated EGFR trafficking to lysosomes and subsequent degradation. Importantly, CD44s levels correlate with EGFR signature and predict poor prognosis in glioblastomas. Because Rab7A facilitates trafficking of many RTKs to lysosomes, our findings identify CD44s as a Rab7A regulator to attenuate RTK degradation.


Asunto(s)
Endosomas/metabolismo , Receptores ErbB/metabolismo , Glioblastoma/patología , Receptores de Hialuranos/metabolismo , Proteínas de Unión al GTP rab/metabolismo , Línea Celular , Receptores ErbB/antagonistas & inhibidores , Glioblastoma/genética , Células HEK293 , Humanos , Receptores de Hialuranos/genética , Lisosomas/metabolismo , Isoformas de Proteínas/genética , Transporte de Proteínas/genética , Transporte de Proteínas/fisiología , Transducción de Señal/genética , Proteínas de Unión al GTP rab/antagonistas & inhibidores , Proteínas de Unión a GTP rab7
16.
Cell Death Differ ; 24(3): 469-480, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-28009353

RESUMEN

Pellino-1 is an E3 ubiquitin ligase acting as a critical mediator for a variety of immune receptor signaling pathways, including Toll-like receptors, interleukin-1 receptor and T-cell receptors. We recently showed that the Pellino-1-transgenic (Tg) mice developed multiple tumors with different subtypes in hematolymphoid and solid organs. However, the molecular mechanism underlying the oncogenic role of Pellino-1 in solid tumors remains unknown. Pellino-1-Tg mice developed adenocarcinoma in the lungs, and Pellino-1 expression was higher in human lung adenocarcinoma cell lines compared with non-neoplastic bronchial epithelial cell lines. Pellino-1 overexpression increased the cell proliferation, survival, colony formation, invasion and migration of lung adenocarcinoma cells, whereas Pellino-1 knock-down showed the opposite effect. Pellino-1 overexpression activated PI3K/Akt and ERK signaling pathways and elicited an epithelial-mesenchymal transition (EMT) phenotype of lung adenocarcinoma cells. Pellino-1-mediated EMT was demonstrated through morphology, the upregulation of Vimentin, Slug and Snail expression and the downregulation of E-cadherin and ß-catenin expression. Notably, Pellino-1 had a direct effect on the overexpression of Snail and Slug through Lys63-mediated polyubiquitination and the subsequent stabilization of these proteins. Pellino-1 expression level was significantly correlated with Snail and Slug expression in human lung adenocarcinoma tissues, and lung tumors from Pellino-1-Tg mice showed Snail and Slug overexpression. The Pellino-1-mediated increase in the migration of lung adenocarcinoma cells was mediated by Snail and Slug expression. Taken together, these results show that Pellino-1 contributes to lung tumorigenesis by inducing overexpression of Snail and Slug and promoting EMT. Pellino-1 might be a potential therapeutic target for lung cancer.


Asunto(s)
Neoplasias Pulmonares/patología , Proteínas Nucleares/metabolismo , Factores de Transcripción de la Familia Snail/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Células A549 , Animales , Línea Celular Tumoral , Cromonas/farmacología , Regulación hacia Abajo/efectos de los fármacos , Transición Epitelial-Mesenquimal , Flavonoides/farmacología , Glucógeno Sintasa Quinasa 3 beta/genética , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Ratones , Ratones Desnudos , Ratones Transgénicos , Morfolinas/farmacología , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Factores de Transcripción de la Familia Snail/antagonistas & inhibidores , Factores de Transcripción de la Familia Snail/genética , Ubiquitina-Proteína Ligasas/antagonistas & inhibidores , Ubiquitina-Proteína Ligasas/genética , Ubiquitinación
17.
Sci Rep ; 6: 30626, 2016 07 28.
Artículo en Inglés | MEDLINE | ID: mdl-27464702

RESUMEN

Potential tumor suppressor p42, ErbB3-binding protein 1 (EBP1) inhibits phosphoinositide 3-kinase (PI3K) activity reducing the p85 regulatory subunit. In this study, we demonstrated that overexpression of p42 promoted not only a reduction of wild type of p85 subunit but also oncogenic mutant forms of p85 which were identified in human cancers. Moreover, we identified the small fragment of C-terminal domain of p42 is sufficient to exhibit tumor suppressing activity of p42-WT, revealing that this small fragment (280-394) of p42 is required for the binding of both HSP70 and CHIP for a degradation of p85. Furthermore, we showed the small fragment of p42 markedly inhibited the tumor growth in mouse xenograft models of brain and breast cancer, resembling tumor suppressing activity of p42. Through identification of the smallest fragment of p42 that is responsible for its tumor suppressor activity, our findings represent a novel approach for targeted therapy of cancers that overexpress PI3K.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Fosfatidilinositol 3-Quinasa Clase Ia/metabolismo , Regulación hacia Abajo , Proteínas de Unión al ARN/metabolismo , Animales , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Proteínas de Unión al ADN , Modelos Animales de Enfermedad , Proteínas del Choque Térmico HSP72/metabolismo , Humanos , Ratones , Proteínas Nucleares/administración & dosificación , Proteínas Nucleares/metabolismo , Unión Proteica , Resultado del Tratamiento , Ubiquitina-Proteína Ligasas/metabolismo
18.
Oncotarget ; 7(27): 41811-41824, 2016 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-27248820

RESUMEN

Pellino-1 is an E3 ubiquitin ligase that mediates immune receptor signaling pathways. The role of Pellino-1 in oncogenesis of lung cancer was investigated in this study. Pellino-1 expression was increased in human lung cancer cell lines compared with non-neoplastic lung cell lines. Pellino-1 overexpression in human lung cancer cells, A549 and H1299 cells, increased the survival and colony forming ability. Pellino-1 overexpression in these cells also conferred resistance to cisplatin- or paclitaxel-induced apoptosis. In contrast, depletion of Pellino-1 decreased the survival of A549 and H1299 cells and sensitized these cells to cisplatin- and paclitaxel-induced apoptosis. Pellino-1 overexpression in A549 and H1299 cells upregulated the expression of inhibitor of apoptosis (IAP) proteins, including cIAP1 and cIAP2, while Pellino-1 depletion downregulated these molecules. Notably, Pellino-1 directly interacted with cIAP2 and stabilized cIAP2 through lysine63-mediated polyubiquitination via its E3 ligase activity. Pellino-1-mediated chemoresistance in lung cancer cells was dependent on the induction of cIAP2. Moreover, a strong positive correlation between Pellino-1 and the cIAP2 expression was observed in human lung adenocarcinoma tissues. Taken together, these results demonstrate that Pellino-1 contributes to lung oncogenesis through the overexpression of cIAP2 and promotion of cell survival and chemoresistance. Pellino-1 might be a novel oncogene and potential therapeutic target in lung cancer.


Asunto(s)
Proteína 3 que Contiene Repeticiones IAP de Baculovirus/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas Nucleares/metabolismo , Poliubiquitina/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Células A549 , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/genética , Proteína 3 que Contiene Repeticiones IAP de Baculovirus/genética , Línea Celular , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Cisplatino/farmacología , Resistencia a Antineoplásicos/genética , Células HCT116 , Células HEK293 , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Lisina/genética , Lisina/metabolismo , Proteínas Nucleares/genética , Paclitaxel/farmacología , Interferencia de ARN , Ubiquitina-Proteína Ligasas/genética , Ubiquitinación , Regulación hacia Arriba
19.
Sci Rep ; 6: 21857, 2016 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-26899247

RESUMEN

Although the essential role of protein kinase B (PKB)/Akt in cell survival signaling has been clearly established, the mechanism by which Akt mediates the cellular response to hydrogen peroxide (H2O2)-induced oxidative stress remains unclear. We demonstrated that Akt attenuated neuronal apoptosis through direct association with histone 2A (H2A) and phosphorylation of H2A at threonine 17. At early time points during H2O2 exposure of PC12 cells and primary hippocampal neurons, when the cells can tolerate the level of DNA damage, Akt was activated and phosphorylated H2A, leading to inhibition of apoptotic death. At later time points, Akt delivered the NAD(+)-dependent protein deacetylase Sirtuin 2 (Sirt 2) to the vicinity of phosphorylated H2A in response to irreversible DNA damage, thereby inducing H2A deacetylation and subsequently leading to apoptotic death. Ectopically expressed T17A-substituted H2A minimally interacted with Akt and failed to prevent apoptosis under oxidative stress. Thus Akt-mediated H2A phosphorylation has an anti-apoptotic function in conditions of H2O2-induced oxidative stress in neurons and PC12 cells.


Asunto(s)
Histonas/genética , Peróxido de Hidrógeno/farmacología , Neuronas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/genética , Treonina/metabolismo , Animales , Apoptosis/efectos de los fármacos , Daño del ADN , Regulación de la Expresión Génica , Hipocampo/citología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Histonas/metabolismo , Neuronas/citología , Neuronas/metabolismo , Estrés Oxidativo , Células PC12 , Fosforilación/efectos de los fármacos , Cultivo Primario de Células , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Transducción de Señal , Sirtuina 2/genética , Sirtuina 2/metabolismo
20.
Stem Cell Res ; 15(3): 598-607, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26513555

RESUMEN

Neural stem cell (NSC)-based carriers have been presented as promising therapeutic tools for the treatment of infiltrative brain tumors due to their intrinsic tumor homing property. They have demonstrated the ability to migrate towards distant tumor microsatellites and effectively deliver the therapeutic payload, thus significantly improving survival in experimental animal models for brain tumor. Despite such optimistic results, the efficacy of NSC-based anti-cancer therapy has been limited due to the restricted tumor homing ability of NSCs. To examine this issue, we investigated the mechanisms of tumor-tropic migration of an FDA-approved NSC line, HB1.F3.CD, by performing a gene expression analysis. We identified vascular endothelial growth factor-A (VEGFA) and membrane-bound matrix metalloproteinase (MMP14) as molecules whose expression are significantly elevated in migratory NSCs. We observed increased expression of VEGF receptor 2 (VEGFR2) in the focal adhesion complexes of migratory NSCs, with downstream activation of VEGFR2-dependent kinases such as p-PLCγ, p-FAK, and p-Akt, a signaling cascade reported to be required for cellular migration. In an in vivo orthotopic glioma xenograft model, analysis of the migratory trail showed that NSCs maintained expression of VEGFR2 and preferentially migrated within the perivascular space. Knockdown of VEGFR2 via shRNAs led to significant downregulation of MMP14 expression, which resulted in inhibited tumor-tropic migration. Overall, our results suggest, the involvement of VEGFR2-regulated MMP14 in the tumor-tropic migratory behavior of NSCs. Our data warrant investigation of MMP14 as a target for enhancing the migratory properties of NSC carriers and optimizing the delivery of therapeutic payloads to disseminated tumor burdens.


Asunto(s)
Terapia Genética/métodos , Glioma/metabolismo , Metaloproteinasa 14 de la Matriz/genética , Metaloproteinasa 14 de la Matriz/metabolismo , Células-Madre Neurales/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Animales , Humanos , Ratones , Células-Madre Neurales/citología
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