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1.
Transl Neurodegener ; 13(1): 4, 2024 01 09.
Artículo en Inglés | MEDLINE | ID: mdl-38195518

RESUMEN

Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly and represents a major clinical challenge in the ageing society. Neuropathological hallmarks of AD include neurofibrillary tangles composed of hyperphosphorylated tau, senile plaques derived from the deposition of amyloid-ß (Aß) peptides, brain atrophy induced by neuronal loss, and synaptic dysfunctions. Death-associated protein kinase 1 (DAPK1) is ubiquitously expressed in the central nervous system. Dysregulation of DAPK1 has been shown to contribute to various neurological diseases including AD, ischemic stroke and Parkinson's disease (PD). We have established an upstream effect of DAPK1 on Aß and tau pathologies and neuronal apoptosis through kinase-mediated protein phosphorylation, supporting a causal role of DAPK1 in the pathophysiology of AD. In this review, we summarize current knowledge about how DAPK1 is involved in various AD pathological changes including tau hyperphosphorylation, Aß deposition, neuronal cell death and synaptic degeneration. The underlying molecular mechanisms of DAPK1 dysregulation in AD are discussed. We also review the recent progress regarding the development of novel DAPK1 modulators and their potential applications in AD intervention. These findings substantiate DAPK1 as a novel therapeutic target for the development of multifunctional disease-modifying treatments for AD and other neurological disorders.


Asunto(s)
Enfermedad de Alzheimer , Anciano , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Proteínas Quinasas Asociadas a Muerte Celular/genética , Péptidos beta-Amiloides , Sistema Nervioso Central , Ovillos Neurofibrilares
2.
Arch Pharm Res ; 46(11-12): 882-896, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37804415

RESUMEN

Breast cancer is one of the major malignancies in women, and most related deaths are due to recurrence, drug resistance, and metastasis. The expression of the mouse double minute 2 (MDM2) oncogene is upregulated in breast cancer; however, its regulatory mechanism has yet to be fully elucidated. Herein, we identified the tumor suppressor death-associated protein kinase 1 (DAPK1) as a novel MDM2 regulator by unbiased peptide library screening. DAPK1 is directly bound to MDM2 and phosphorylates it at Thr419. DAPK1-mediated MDM2 phosphorylation promoted its protein degradation via the ubiquitin-proteasome pathway, resulting in upregulated p53 expression. DAPK1 overexpression, but not its kinase activity-deficient form, decreased colony formation and increased doxorubicin-induced cell death; however, DAPK1 knockdown produced the opposite effects in human breast cancer cells. In a xenograft tumorigenesis assay, DAPK1 overexpression significantly reduced tumor formation, whereas inhibition of DAPK1 kinase activity reduced its antitumorigenic effect. Finally, DAPK1 expression was negatively correlated with MDM2 levels in human breast cancer tissues. Thus, these results suggest that DAPK1-mediated MDM2 phosphorylation and its protein degradation may contribute to its antitumorigenic function in breast cancer.


Asunto(s)
Neoplasias de la Mama , Proteína p53 Supresora de Tumor , Animales , Femenino , Humanos , Ratones , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Proteínas Quinasas Asociadas a Muerte Celular/metabolismo , Fosforilación , Estabilidad Proteica , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteína p53 Supresora de Tumor/metabolismo
3.
Int J Mol Sci ; 20(5)2019 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-30832444

RESUMEN

Several reports have shown that thymoquinone (TQ) effectively attenuates angiogenesis in cancer cells, resulting in suppression of tumor growth. However, it is not yet clear whether TQ reduces hypoxia-inducible factor-1α (HIF-1α) expression in hypoxic cancer cells. Here, we found that TQ was a novel HIF-1α inhibitor through hypoxia response element (HRE)-luciferase assay-based large screening by using 502 natural compounds containing chemical library. TQ reduced HIF-1α protein levels in renal cancer cells; however, it did not affect the HIF-1α protein levels in the presence of proteasome inhibitor, MG132, indicating that the reduction effects of TQ on HIF-1α protein are mediated via the ubiquitination-proteasome dependent pathway. TQ boosted HIF-1α protein degradation, and the mechanism was revealed by inhibiting interaction between HSP90 and HIF-1α. TQ suppressed downstream genes of HIF-1α, indicating negative impact of TQ on HIF-1α transcriptional activities. In addition, TQ altered glucose, lactate, and ATP levels, leading to anaerobic metabolic disturbance. TQ induced apoptosis in hypoxic cancer cells as determined by crystal violet staining and flow cytometry for annexin V-stained cells. Taken together, we suggested that TQ is a potential anticancer agent targeting HIF-1α.


Asunto(s)
Antineoplásicos/farmacología , Benzoquinonas/farmacología , Glucólisis , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Apoptosis/efectos de los fármacos , Hipoxia de la Célula , Línea Celular Tumoral , Humanos , Neoplasias Renales/metabolismo
4.
Oncogenesis ; 8(3): 12, 2019 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-30783083

RESUMEN

In cancer, activation of X-box binding protein (XBP1) has a critical role in tumorigenesis and cancer progression. Transcriptional regulatory mechanism of XBP1 in cancer development has been well known, however, regulation of ubiquitination and degradation of XBP1 has not been elucidated yet. Here we show that Fbw7, a substrate recognition component of the SKP1-Cullin-F-box-type E3 ligase, interacts with XBP1 in a phosphorylation-dependent manner, and facilitates XBP1 ubiquitination and protein degradation. Moreover, Fbw7 inhibits oncogenic pathways including NF-κB, AP1, and Myc induced by XBP1. Interestingly, XBP1 negatively regulates transcription of Fbw7 via a feedback mechanism through NF-κB/E2F-1 axis signaling pathway, suggesting that overexpression of XBP1s may contribute to low level of Fbw7 expression in human cancers. Therefore, a negative feedback loop between Fbw7 and XBP1 contributes to the regulation of tumor development and can be an attractive target for novel therapy in cancers.

5.
Nat Cell Biol ; 21(5): 662-663, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30783264

RESUMEN

In the version of this Article originally published, the labels for Rictor and mTOR in the whole cell lysate (WCL) blots were swapped in Fig. 3b and the mTOR blot was placed upside down. Unprocessed blots of mTOR were also missing from Supplementary Fig. 9. The corrected Figs are shown below. In addition, control blots for the mTOR antibody (Cell Signalling Technology #2972) were also missing. These are now provided below, as Fig. 9, and show that the lower band is likely non-specific.

6.
Int J Mol Sci ; 19(11)2018 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-30388809

RESUMEN

YAP/TAZ, a transcriptional co-activator of Hippo pathway, has emerged as a central player in vessel homeostasis such as sprouting angiogenesis and vascular barrier stabilization, during development. However, the role of YAP/TAZ in pathological angiogenesis remains unclear. Here, we demonstrated that YAP/TAZ is a critical mediator in leukocyte-endothelial adhesion induced by the vascular inflammatory cytokine TNF-α. YAP/TAZ was dephosphorylated, translocated from the cytosol to the nucleus, and activated by TNF-α in endothelial cells. A specific inhibitor of Rho GTPases suppressed the TNF-α-induced dephosphorylation of YAP. Knockdown of YAP/TAZ using siRNA significantly reduced the expression of the leukocyte adhesion molecule VCAM1 induced by TNF-α. The adhesion of monocytes to endothelial cells was also markedly reduced by YAP/TAZ silencing. However, knockdown of YAP/TAZ did not affect TNF-α-induced NF-κB signaling. Overall, these results suggest that YAP/TAZ plays critical roles in regulating TNF-α-induced endothelial cell adhesive properties without affecting the NF-κB pathway, and implicate YAP/TAZ as a potential therapeutic target for treating inflammatory vascular diseases.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Células Endoteliales de la Vena Umbilical Humana/citología , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Leucocitos/citología , Fosfoproteínas/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Molécula 1 de Adhesión Celular Vascular/metabolismo , Adhesión Celular/efectos de los fármacos , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Técnicas de Silenciamiento del Gen , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Molécula 1 de Adhesión Intercelular/metabolismo , Leucocitos/efectos de los fármacos , Leucocitos/metabolismo , FN-kappa B/metabolismo , Fosforilación , Transducción de Señal , Transactivadores , Factores de Transcripción , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ , Proteínas Señalizadoras YAP , Proteínas de Unión al GTP rho/metabolismo
7.
Int J Mol Sci ; 19(10)2018 Oct 12.
Artículo en Inglés | MEDLINE | ID: mdl-30321984

RESUMEN

Reduced therapeutic efficacy of sorafenib, a first-generation multikinase inhibitor, is often observed during the treatment of advanced hepatocellular carcinoma (HCC). Emodin is an active component of Chinese herbs, and is effective against leukemia, lung cancer, colon cancer, pancreatic cancer, and HCC; however, the sensitizing effect of emodin on sorafenib-based HCC therapy has not been evaluated. Here, we demonstrate that emodin significantly improved the anti-cancer effect of sorafenib in HCC cells, such as HepG2, Hep3B, Huh7, SK-HEP-1, and PLC/PRF5. Mechanistically, emodin inhibits sterol regulatory element-binding protein-2 (SREBP-2) transcriptional activity, which suppresses cholesterol biosynthesis and oncogenic protein kinase B (AKT) signaling. Additionally, attenuated cholesterol synthesis and oncogenic AKT signaling inactivated signal transducer and activator of transcription 3 (STAT3), an oncogenic transcription factor. Furthermore, emodin synergistically increased cell cycle arrest in the G1 phase and apoptotic cells in the presence of sorafenib. Animal models xenografted with HepG2 or SK-HEP-1 cells also showed that the combination of emodin and sorafenib was sufficient to inhibit tumor growth. Overall, these results suggested that the combination of emodin and sorafenib may offer a potential therapy for patients with advanced HCC.


Asunto(s)
Carcinoma Hepatocelular/tratamiento farmacológico , Colesterol/metabolismo , Emodina/administración & dosificación , Neoplasias Hepáticas/tratamiento farmacológico , Sorafenib/administración & dosificación , Animales , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Sinergismo Farmacológico , Emodina/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Ratones , Proteínas Proto-Oncogénicas c-akt/genética , Transducción de Señal/efectos de los fármacos , Sorafenib/farmacología , Proteína 2 de Unión a Elementos Reguladores de Esteroles/genética , Ensayos Antitumor por Modelo de Xenoinjerto
8.
Oxid Med Cell Longev ; 2018: 8275256, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29849917

RESUMEN

As life expectancy increases, elderly populations tend to spend an increasing number of years in poor health, with chronic age-related diseases and disability. Therefore, the development of therapeutic strategies to treat or prevent multiple pathophysiological conditions in the elderly may improve health-adjusted life expectancy and alleviate the potential economic and social burdens arising from age-related diseases. Bioactive natural products might represent promising new drug candidates for the treatment of many chronic age-related diseases, including cancer, Alzheimer's disease, cardiovascular disease, obesity, and liver disease. Here, we discuss a therapeutic option using saikosaponins, which are triterpene saponins isolated from Bupleurum, against a variety of age-related diseases. Understanding the underlying mechanisms of natural products like saikosaponins in the treatment of age-related diseases may help in the development of diverse natural product-derived compounds that may be effective against a number of chronic health problems.


Asunto(s)
Enfermedades Cardiovasculares/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Ácido Oleanólico/análogos & derivados , Saponinas/uso terapéutico , Apoptosis/efectos de los fármacos , Enfermedades Cardiovasculares/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Humanos , Hepatopatías/tratamiento farmacológico , Hepatopatías/patología , Neoplasias/patología , Enfermedades Neurodegenerativas/patología , Obesidad/patología , Obesidad/prevención & control , Ácido Oleanólico/química , Ácido Oleanólico/farmacología , Ácido Oleanólico/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Saponinas/química , Saponinas/farmacología
9.
Oncotarget ; 8(59): 100433-100448, 2017 Nov 21.
Artículo en Inglés | MEDLINE | ID: mdl-29245990

RESUMEN

Saikosaponin a (SSa), a bioactive phytochemical from Bupleurum, triggers sequential caspase-2 and caspase-8 activation, and thereby induces caspase-mediated apoptosis in human colon carcinoma (HCC) cells. However, the upstream mechanism of caspase-2 activation remains unknown. Therefore, we investigated the signaling mechanisms underlying SSa-induced caspase activation and apoptosis in HCC cells. SSa treatment triggered marked antitumor effects, especially in HCC cells, in a cell culture model and a mouse xenograft model. SSa also induced the activation of several endoplasmic reticulum (ER) stress signals. Specifically, caspase-4, a critical regulator of ER stress-induced apoptosis, was activated significantly after SSa treatment. Mechanistically, selective inhibition of caspase-4 suppressed SSa-induced apoptosis, colony inhibition, and the activation of caspase-3, -8, and -2, but not vice versa. Consistent with the important role of caspase-2 in the DNA damage response, SSa induced DNA damage, as evidenced by a cytokinesis-block micronucleus assay, single-cell gel electrophoresis, and an increase in the levels of γ-H2AX, a DNA damage marker. Moreover, inhibition of caspase-4 activation inhibited SSa-induced histone H2AX phosphorylation. Taken together, these results suggest that caspase-4 is an upstream regulator of SSa-induced DNA damage and caspase activation in HCC cells. Given that SSa-induced apoptosis appeared to be specific to certain cell types including HCC cells, SSa may be a promising cancer therapy agent in certain types of cancer.

10.
Curr Pharm Des ; 23(29): 4259-4280, 2017 11 16.
Artículo en Inglés | MEDLINE | ID: mdl-28911303

RESUMEN

Phosphorylation, the addition of a phosphate group to a molecule, is an effective way of regulating the biological properties of that molecule. Protein phosphorylation is a post-translational modification of proteins and affects cellular signaling transduction. Protein kinases induce phosphorylation by catalyzing the transfer of phosphate groups to serine, threonine, and tyrosine residues on protein substrates. Consistent with their roles in cancer, protein kinases have emerged as one of the most clinically useful target molecules in pharmacological cancer therapy. Intrinsic or acquired resistance of cancers against anti-cancer therapeutics, such as ionizing radiation, is a major obstacle for the effective treatment of many cancers. In this review, we describe key aspects of various kinases acting on proteins. We also discuss the roles of protein kinases in the pathophysiology and treatment of cancer. Because protein kinases correlate with radiation resistance in various types of cancer, we focus on several kinases responsible for radiation resistance and/or sensitivity and their therapeutic implications. Finally, we suggest some ongoing radiation-sensitization strategies using genetic loss and/or kinase inhibitors that can counteract radiation resistance-related protein kinases.


Asunto(s)
Neoplasias/radioterapia , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Quinasas/efectos de la radiación , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Humanos , Neoplasias/tratamiento farmacológico , Radiación Ionizante
11.
Int J Mol Sci ; 18(3)2017 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-28257048

RESUMEN

Recent studies have shown that vanillin has anti-cancer, anti-mutagenic, and anti-metastatic activity; however, the precise molecular mechanism whereby vanillin inhibits metastasis and cancer progression is not fully elucidated. In this study, we examined whether vanillin has anti-cancer and anti-metastatic activities via inhibition of hypoxia-inducible factor-1α (HIF-1α) in A2058 and A375 human malignant melanoma cells. Immunoblotting and quantitative real time (RT)-PCR analysis revealed that vanillin down-regulates HIF-1α protein accumulation and the transcripts of HIF-1α target genes related to cancer metastasis including fibronectin 1 (FN1), lysyl oxidase-like 2 (LOXL2), and urokinase plasminogen activator receptor (uPAR). It was also found that vanillin significantly suppresses HIF-1α mRNA expression and de novo HIF-1α protein synthesis. To understand the suppressive mechanism of vanillin on HIF-1α expression, chromatin immunoprecipitation was performed. Consequently, it was found that vanillin causes inhibition of promoter occupancy by signal transducer and activator of transcription 3 (STAT3), but not nuclear factor-κB (NF-κB), on HIF1A. Furthermore, an in vitro migration assay revealed that the motility of melanoma cells stimulated by hypoxia was attenuated by vanillin treatment. In conclusion, we demonstrate that vanillin might be a potential anti-metastatic agent that suppresses metastatic gene expression and migration activity under hypoxia via the STAT3-HIF-1α signaling pathway.


Asunto(s)
Benzaldehídos/farmacología , Movimiento Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Melanoma/genética , Melanoma/metabolismo , Factor de Transcripción STAT3/metabolismo , Línea Celular Tumoral , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Regiones Promotoras Genéticas , Unión Proteica , ARN Mensajero/genética , ARN Mensajero/metabolismo , Activación Transcripcional
12.
Cell Death Differ ; 24(2): 238-250, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-28141794

RESUMEN

Death-associated protein kinase 1 (DAPK1) has been shown to have important roles in neuronal cell death in several model systems and has been implicated in multiple diseases, including Alzheimer's disease (AD). However, little is known about the molecular mechanisms by which DAPK1 signals neuronal cell death. In this study, N-myc downstream-regulated gene 2 (NDRG2) was identified as a novel substrate of DAPK1 using phospho-peptide library screening. DAPK1 interacted with NDRG2 and directly phosphorylated the Ser350 residue in vitro and in vivo. Moreover, DAPK1 overexpression increased neuronal cell death through NDRG2 phosphorylation after ceramide treatment. In contrast, inhibition of DAPK1 by overexpression of a DAPK1 kinase-deficient mutant and small hairpin RNA, or by treatment with a DAPK1 inhibitor significantly decreased neuronal cell death, and abolished NDRG2 phosphorylation in cell culture and in primary neurons. Furthermore, NDRG2-mediated cell death by DAPK1 was required for a caspase-dependent poly-ADP-ribose polymerase cleavage. In addition, DAPK1 ablation suppressed ceramide-induced cell death in mouse brain and neuronal cell death in Tg2576 APPswe-overexpressing mice. Finally, levels of phosphorylated NDRG2 Ser350 and DAPK1 were significantly increased in human AD brain samples. Thus, phosphorylation of NDRG2 on Ser350 by DAPK1 is a novel mechanism activating NDRG2 function and involved in neuronal cell death regulation in vivo.


Asunto(s)
Proteínas Quinasas Asociadas a Muerte Celular/metabolismo , Proteínas/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Clorometilcetonas de Aminoácidos/farmacología , Animales , Apoptosis/efectos de los fármacos , Encéfalo/metabolismo , Caspasa 3/química , Caspasa 3/metabolismo , Células Cultivadas , Ceramidas/farmacología , Proteínas Quinasas Asociadas a Muerte Celular/antagonistas & inhibidores , Proteínas Quinasas Asociadas a Muerte Celular/genética , Células HEK293 , Células HeLa , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuronas/citología , Neuronas/metabolismo , Fosforilación/efectos de los fármacos , Poli(ADP-Ribosa) Polimerasas/metabolismo , Proteínas/antagonistas & inhibidores , Proteínas/genética , Interferencia de ARN
13.
Eur J Cancer ; 70: 48-61, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-27883926

RESUMEN

Salmonella have been experimentally used as anti-cancer agents, because they show selective growth in tumours. In this study, we genetically modified attenuated Salmonella typhimurium to express and secrete interferon-gamma (IFN-γ) as a tumouricidal agent to enhance the therapeutic efficacy of Salmonella. IFN-γ was fused to the N-terminal region (residues 1-160) of SipB (SipB160) for secretion from bacterial cells. Attenuated S. typhimurium expressing recombinant IFN-γ (S. typhimurium (IFN-γ)) invaded the melanoma cells and induced cytotoxicity. Subcutaneous administration of S. typhimurium (IFN-γ) also efficiently inhibited tumour growth and prolonged the survival of C57BL/6 mice bearing B16F10 melanoma compared with administration of phosphate-buffered saline (PBS), unmodified S. typhimurium or S. typhimurium expressing empty vector (S. typhimurium [Vec]) in a natural killer (NK) cell-dependent manner. Moreover, genetically modified Salmonella, including S. typhimurium (IFN-γ), showed little toxicity to normal tissues with no observable adverse effects. However, S. typhimurium (IFN-γ)-mediated tumour suppression was attributed to direct killing of tumour cells rather than to stable anti-tumour immunity. Collectively, these results suggest that tumour-targeted therapy using S. typhimurium (IFN-γ) has potential for melanoma treatment.


Asunto(s)
Inmunoterapia/métodos , Interferón gamma/biosíntesis , Melanoma Experimental/terapia , Organismos Modificados Genéticamente/metabolismo , Salmonella typhimurium/metabolismo , Neoplasias Cutáneas/terapia , Animales , Western Blotting/métodos , Modelos Animales de Enfermedad , Humanos , Inmunidad Innata , Células Asesinas Naturales/inmunología , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Salmonella typhimurium/patogenicidad , Células Tumorales Cultivadas
14.
Molecules ; 23(1)2017 Dec 24.
Artículo en Inglés | MEDLINE | ID: mdl-29295560

RESUMEN

Fascaplysin, a natural product isolated from marine sponges, is a potential candidate for the development of anti-cancer drugs. However, the mechanism underlying its therapeutic effect of strengthening anti-cancer efficacy of other drugs is poorly understood. Here, we found that fascaplysin increases phosphorylation of protein kinase B (PKB), also known as AKT, and adenosine monophosphate-activated protein kinase (AMPK), which are considered therapeutic targets for cancer treatment due to their anti-apoptotic or pro-survival functions in cancer. A cell viability assay revealed that pharmacological suppression of AKT using LY294002 enhanced the anti-cancer effect of fascaplysin in various cancer cells. Similarly, fascaplysin was observed to have improved anti-cancer effects in combination with compound C, a selective AMPK inhibitor. Another challenge showed that fascaplysin increased the efficacy of methotrexate (MTX)-mediated cancer therapy by suppressing genes related to folate and purine metabolism. Overall, these results suggest that fascaplysin may be useful for improving the anti-cancer efficacy of targeted anti-cancer drugs, such as inhibitors of phosphoinositide 3-kinase AKT signaling, and chemotherapeutic agents, such as MTX.


Asunto(s)
Adenilato Quinasa/antagonistas & inhibidores , Antineoplásicos/farmacología , Indoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Adenilato Quinasa/metabolismo , Línea Celular Tumoral , Daño del ADN , Sinergismo Farmacológico , Activación Enzimática/efectos de los fármacos , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Metotrexato/farmacología , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Estrés Fisiológico/efectos de los fármacos
15.
Hum Mol Genet ; 25(12): 2498-2513, 2016 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-27094130

RESUMEN

Extracellular deposition of amyloid-beta (Aß) peptide, a metabolite of sequential cleavage of amyloid precursor protein (APP), is a critical step in the pathogenesis of Alzheimer's disease (AD). While death-associated protein kinase 1 (DAPK1) is highly expressed in AD brains and its genetic variants are linked to AD risk, little is known about the impact of DAPK1 on APP metabolism and Aß generation. In this study, we demonstrated a novel effect of DAPK1 in the regulation of APP processing using cell culture and mouse models. DAPK1, but not its kinase deficient mutant (K42A), significantly increased human Aß secretion in neuronal cell culture models. Moreover, knockdown of DAPK1 expression or inhibition of DAPK1 catalytic activity significantly decreased Aß secretion. Furthermore, DAPK1, but not K42A, triggered Thr668 phosphorylation of APP, which may initiate and facilitate amyloidogenic APP processing leading to the generation of Aß. In Tg2576 APPswe-overexpressing mice, knockout of DAPK1 shifted APP processing toward non-amyloidogenic pathway and decreased Aß generation. Finally, in AD brains, elevated DAPK1 levels showed co-relation with the increase of APP phosphorylation. Combined together, these results suggest that DAPK1 promotes the phosphorylation and amyloidogenic processing of APP, and that may serve a potential therapeutic target for AD.


Asunto(s)
Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Proteínas Quinasas Asociadas a Muerte Celular/genética , Neuronas/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/biosíntesis , Animales , Encéfalo/metabolismo , Encéfalo/patología , Proteínas Quinasas Asociadas a Muerte Celular/antagonistas & inhibidores , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Humanos , Ratones , Neuronas/patología , Fosforilación
16.
Biomed Res Int ; 2016: 8432759, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26989693

RESUMEN

Diabetes and obesity represent the major health problems and the most age-related metabolic diseases. Protein-tyrosine phosphatase 1B (PTP1B) has emerged as an important regulator of insulin signal transduction and is regarded as a pharmaceutical target for metabolic disorders. To find novel natural materials presenting therapeutic activities against diabetes and obesity, we screened various herb extracts using a chip screening allowing the determination of PTP1B inhibitory effects of the tested compounds using insulin receptor (IR) as the substrate. Cudrania tricuspidata leaves (CTe) had a strong inhibitory effect on PTP1B activity and substantially inhibited fat accumulation in 3T3-L1 cells. CTe was orally administrated to diet-induced obesity (DIO) mice once daily for 3 weeks after which changes in glucose, insulin metabolism, and fat accumulation were examined. Hepatic enzyme markers (aspartate aminotransferase, AST, and alanine aminotransferase, ALT) and total fat mass and triglyceride levels decreased in CTe-treated mice, whereas body weight and total cholesterol concentration slightly decreased. CTe increased the phosphorylation of IRS-1 and Akt in liver tissue. Furthermore, CTe treatment significantly lowered blood glucose levels and improved insulin secretion in DIO mice. Our results strongly suggest that CTe may represent a promising therapeutic substance against diabetes and obesity.


Asunto(s)
Diabetes Mellitus/tratamiento farmacológico , Obesidad/tratamiento farmacológico , Extractos Vegetales/administración & dosificación , Proteína Tirosina Fosfatasa no Receptora Tipo 1/biosíntesis , Células 3T3-L1 , Animales , Diabetes Mellitus/genética , Diabetes Mellitus/patología , Humanos , Insulina/sangre , Resistencia a la Insulina/genética , Hígado/efectos de los fármacos , Hígado/patología , Ratones , Ratones Obesos , Moraceae/química , Obesidad/genética , Obesidad/patología , Extractos Vegetales/química , Transducción de Señal/efectos de los fármacos
17.
Biochem Biophys Res Commun ; 470(1): 181-186, 2016 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-26768359

RESUMEN

USP7 is a deubiquitinating enzyme that involves the ubiquitin proteasome system (UPS) to maintain regulation of protein synthesis and degradation. The well-known substrate of USP7 is the Mdm2-p53 complex. In fact, several studies have reported that functional inhibition of USP7 induces cancer cell apoptosis through activation of p53. However, the contribution of oxidative or endoplasmic reticulum (ER) stress, which is commonly induced by inhibition of the UPS for USP7 inhibitor-mediated apoptosis in cancer cells, has not been investigated. In contrast to previous reports, we show that p53 is not critical during USP7 inhibitor-induced apoptosis in several cancer cells. Inhibition of deubiquitinating enzyme activities by USP7 inhibitors causes ER stress by accumulating polyubiquitinated proteins in cancer cells. Furthermore, we demonstrate that USP7 inhibitors increase intracellular reactive oxygen species and mainly cause cancer cell apoptosis. Taken together, our results reveal that oxidative and ER stress, rather than the Mdm2-p53 axis, mainly contributes to USP7 inhibitor-mediated apoptosis in cancer cells.


Asunto(s)
Antineoplásicos/administración & dosificación , Apoptosis/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Neoplasias Experimentales/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ubiquitina Tiolesterasa/metabolismo , Línea Celular Tumoral , Humanos , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Especies Reactivas de Oxígeno/metabolismo , Ubiquitina Tiolesterasa/antagonistas & inhibidores , Peptidasa Específica de Ubiquitina 7 , Ubiquitinación/efectos de los fármacos
18.
J Neurochem ; 136(6): 1232-1245, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26710244

RESUMEN

Alzheimer's disease (AD) is a chronic neurodegenerative disease and the risk of developing it increases with advancing age. In this study, we investigated the protective effects of saikosaponin C (SSc), one of the main bioactive components produced by the traditional Chinese herb, radix bupleuri, the root of Bupleurum falcatum, against AD in various neuronal models. Interestingly, we found that SSc has dual effects on AD by targeting amyloid beta (Aß) and tau, two key proteins in AD. SSc significantly suppressed the release of both Aß peptides 1-40 and 1-42 into cell culture supernatants, though it does not affect BACE1 activity and expression. SSc also inhibited abnormal tau phosphorylation at multiple AD-related residues. Moreover, SSc seems to have beneficial effects on cellular tau function; it accelerated nerve growth factor-mediated neurite outgrowth and increased the assembly of microtubules. In addition, SSc increased synaptic marker proteins such as synaptophysin and PSD-95. Considering its various biological activities, our results suggest that SSc might be a novel therapeutic tool for treating human AD and other neurodegenerative diseases. Tau and amyloid beta are two key features in Alzheimer's disease. Saikosaponin C, an active component of Bupleuri Radix, inhibits abnormal tau phosphorylation and amyloid beta production, thereby promoting synaptic integrity. Saikosaponin C also prevents amyloid beta-induced apoptosis in brain vascular endothelial cells. Therefore, Saikosaponin C may provide a new therapeutic strategy for treatment of neurodegenerative diseases, including Alzheimer's disease.

19.
Int J Oncol ; 48(1): 399-408, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26573871

RESUMEN

Recent studies have shown anticancer activity of apigenin by suppressing glucose transporter 1 (GLUT1) expression in cultured cancer cells; however, it is not clear whether apigenin can suppress glucose metabolism in lung cancer cells or sensitize them to inhibition of glutamine utilization-mediated apoptosis through metabolic and oxidative stress. We show that apigenin significantly decreases GLUT1 expression in mice. Furthermore, we demonstrate that apigenin induces growth retardation and apoptosis through metabolic and oxidative stress caused by suppression of glucose utilization in lung cancer cells. The underlying mechanisms were defined that the anticancer effects of apigenin were reversed by ectopic GLUT1 overexpression and galactose supplementation, through activation of pentose phosphate pathway-mediated NADPH generation. Importantly, we showed that severe metabolic stress using a glutaminase inhibitor, compound 968, was involved in the mechanism of sensitization by apigenin. Taken together, the combination of apigenin with inhibitors of glutamine metabolism may provide a promising therapeutic strategy for cancer treatment.


Asunto(s)
Apoptosis/efectos de los fármacos , Transportador de Glucosa de Tipo 1/biosíntesis , Neoplasias Pulmonares/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Animales , Apigenina/administración & dosificación , Benzofenantridinas/administración & dosificación , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Transportador de Glucosa de Tipo 1/antagonistas & inhibidores , Transportador de Glucosa de Tipo 1/genética , Glutamina/genética , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , NADP/metabolismo , Especies Reactivas de Oxígeno/metabolismo
20.
Int J Mol Sci ; 16(11): 26880-913, 2015 Nov 10.
Artículo en Inglés | MEDLINE | ID: mdl-26569225

RESUMEN

Ionizing radiation (IR), such as X-rays and gamma (γ)-rays, mediates various forms of cancer cell death such as apoptosis, necrosis, autophagy, mitotic catastrophe, and senescence. Among them, apoptosis and mitotic catastrophe are the main mechanisms of IR action. DNA damage and genomic instability contribute to IR-induced cancer cell death. Although IR therapy may be curative in a number of cancer types, the resistance of cancer cells to radiation remains a major therapeutic problem. In this review, we describe the morphological and molecular aspects of various IR-induced types of cell death. We also discuss cytogenetic variations representative of IR-induced DNA damage and genomic instability. Most importantly, we focus on several pathways and their associated marker proteins responsible for cancer resistance and its therapeutic implications in terms of cancer cell death of various types and characteristics. Finally, we propose radiation-sensitization strategies, such as the modification of fractionation, inflammation, and hypoxia and the combined treatment, that can counteract the resistance of tumors to IR.


Asunto(s)
Aberraciones Cromosómicas , Terapia Combinada/métodos , Rayos gamma/uso terapéutico , Neoplasias/terapia , Tolerancia a Radiación/efectos de los fármacos , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Apoptosis/genética , Apoptosis/efectos de la radiación , Autofagia/genética , Autofagia/efectos de la radiación , Análisis Citogenético , Daño del ADN/efectos de la radiación , Inestabilidad Genómica , Humanos , Mitosis/efectos de la radiación , Necrosis/genética , Necrosis/patología , Neoplasias/genética , Neoplasias/patología , Terapia por Rayos X
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