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1.
Cancer Discov ; 2024 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-38563585

RESUMEN

Glioblastoma (GBM) exhibits profound metabolic plasticity for survival and therapeutic resistance, while the underlying mechanisms remain unclear. Here, we show that GBM stem cells (GSCs) reprogram the epigenetic landscape by producing substantial amounts of phosphocreatine (PCr). This production is attributed to the elevated transcription of brain-type creatine kinase (CKB), mediated by Zinc finger E-box binding homeobox 1 (ZEB1). PCr inhibits the poly-ubiquitination of the chromatin regulator bromodomain containing protein 2 (BRD2) by outcompeting the E3 ubiquitin ligase SPOP for BRD2 binding. Pharmacological disruption of PCr biosynthesis by cyclocreatine leads to BRD2 degradation and a decrease in its targets' transcription, which inhibits chromosome segregation and cell proliferation. Notably, cyclocreatine treatment significantly impedes tumor growth and sensitizes tumors to a BRD2 inhibitor in mouse GBM models without detectable side effects. These findings highlight that high production of PCr is a druggable metabolic feature of GBM and a promising therapeutic target for GBM treatment.

2.
Cell Stem Cell ; 29(11): 1531-1546.e7, 2022 Nov 03.
Artículo en Inglés | MEDLINE | ID: mdl-36265493

RESUMEN

The communication between glioblastoma stem cells (GSCs) and the surrounding microenvironment is a prominent feature accounting for the aggressive biology of glioblastoma multiforme (GBM). However, the mechanisms by which GSCs proactively drive interactions with microenvironment is not well understood. In this study, we interrogated metabolites that are preferentially secreted from GSCs and found that GSCs produce and secrete histamine to shape a pro-angiogenic tumor microenvironment. This histamine-producing ability is attributed to H3K4me3 modification-activated histidine decarboxylase (HDC) transcription via MYC. Notably, HDC is highly expressed in GBM, which is associated with poor survival of these patients. GSC-secreted histamine activates endothelial cells by triggering a histamine H1 receptor (H1R)-Ca2+-NF-κB axis, thereby promoting angiogenesis and GBM progression. Importantly, pharmacological blockage of H1R using antihistamines impedes the growth of GBM xenografts in mice. Our findings establish that GSC-specific metabolite secretion remodels the tumor microenvironment and highlight histamine targeting as a potential strategy for GBM therapy.


Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Humanos , Ratones , Animales , Glioblastoma/patología , Histamina/metabolismo , Microambiente Tumoral , Neoplasias Encefálicas/patología , Células Endoteliales/metabolismo , Células Madre Neoplásicas/patología , Línea Celular Tumoral
3.
Environ Pollut ; 313: 120150, 2022 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-36103943

RESUMEN

Some organophosphate di-esters (di-OPEs) have been found to be more toxic than their respective tri-esters. The environmental occurrence of di-OPEs remains largely unclear. A total of 106 water samples, including 56 drinking water (bottled, barreled, and tap water) and 50 surface water (lake and river) samples were collected and analyzed for 10 organophosphate tri-esters (tri-OPEs) and 7 di-OPEs. The concentrations (range (median)) of ∑7di-OPE were 2.8-22 (9.7), 1.1-5.8 (2.6), 3.7-250 (120), 13-410 (220), and 92-930 (210) ng/L in bottled water, barreled water, tap water, lake water, and river water, respectively. In all types of water samples, tris(1-chloro-2-propyl) phosphate was the dominant tri-OPE compound. Diphenyl phosphate was the predominant di-OPE compound in tap water and surface water, while di-n-butyl phosphate and bis(2-ethylhexyl) phosphate was the dominant compound in bottled water and barreled water, respectively. Source analysis suggested diverse sources of di-OPEs, including industrial applications, effluents of municipal wastewater treatment plants, degradation from tri-OPEs during production/usage and under natural environmental conditions. The non-carcinogenic and carcinogenic risks of OPEs were lower than the theoretical threshold of risk, indicating the human health risks to OPEs via drinking water consumption were negligible. More studies are needed to explore environmental behaviors of di-OPEs in the aquatic environment and to investigate ecological risks.


Asunto(s)
Agua Potable , Retardadores de Llama , Alquinos , China , Agua Potable/análisis , Monitoreo del Ambiente , Ésteres/análisis , Retardadores de Llama/análisis , Humanos , Lagos/análisis , Organofosfatos/análisis , Fosfatos/análisis , Ríos
4.
Front Oncol ; 11: 751792, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34868955

RESUMEN

Glioma stem-like cells (GSCs) are a subset of tumor cells that initiate malignant growth and promote the therapeutic resistance of glioblastoma, the most lethal primary brain tumor. Ribosome biogenesis is an essential cellular process to maintain cell growth, but its regulatory mechanism in GSCs remains largely unknown. Here, we show that WD repeat domain 12 (WDR12), a component of the Pes1-Bop1 complex (PeBoW), is required for ribosome biogenesis in GSCs. WDR12 is preferentially expressed in GSCs compared to non-stem tumor cells and normal brain cells. High levels of WDR12 are associated with glioblastoma progression and poor prognosis. Silencing WDR12 results in the degradation of PeBoW complex components and prevents the maturation of 28S rRNA, thereby inhibiting ribosome biogenesis in GSCs. Subsequently, WDR12 depletion compromises GSC proliferation, inhibits GSC-derived orthotopic tumor growth, and extends animal survival. Together, our results suggest that WDR12 is crucial for ribosome biogenesis in GSCs, and is thus a potential target for GSC-directed therapy of glioblastoma.

5.
Oncol Lett ; 21(4): 329, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33692861

RESUMEN

Tumor mutation burden (TMB) is an independent indicator used to select patients sensitive to immunotherapy. The present study aimed to investigate the clinicopathological and molecular characteristics of patients with hypermutant lung cancer to identify an economical, simple and complementary method for predicting TMB and immunotherapy responses. In total, 1,000 patients with lung cancer were randomly selected, and their samples were submitted to next-generation sequencing, with their TMB status reviewed. The threshold of hypermutation was set to 17.24 mutations (muts)/Mb. The proportion of smokers was higher in the hypermutant cohort (n=67) compared with in the non-hypermutant cohort (n=933; 85.1 vs. 46.6%; P<0.0001). Compared with in the non-hypermutant cohort, the proportion of squamous cell carcinoma cases and small cell lung cancer cases was higher in the hypermutant cohort (22.4 vs. 13.1% and 6.0 vs. 2.6%, respectively). In addition, compared with in the non-hypermutant cohort, mutations in the low-density lipoprotein receptor-related protein 1B were more frequently observed in the hypermutant cohort (67.2 vs. 14.3%; P<0.0001). A similar trend was obtained for all genes tested, except for the EGFR gene. Furthermore, in the hypermutant cohort, the prevalence of microsatellite instability was extremely high (9.0%). The mutation frequency in DNA damage response (DDR) genes was notably higher in the hypermutant cohort, where several DDR-associated genes were enriched, compared with in the non-hypermutant cohort. The enrichment analysis revealed a strong association between mutations in Notch signaling and high TMB. To the best of our knowledge, the present study is the first to comprehensively investigate the clinical and genetic characteristics of patients with hypermutant lung cancer in a Chinese population. The results of the current study suggested that hypermutant lung cancer exerted distinctive clinical and genetic features, which may be used as complementary indicators for screening patients sensitive to immunotherapy.

6.
J Virol ; 93(4)2019 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-30463971

RESUMEN

Dengue virus (DENV) utilizes host factors throughout its life cycle. In this study, we identified RNA helicase A (RHA), a member of the DEAD/H helicase family, as an important host factor of DENV. In response to DENV2 infection, nuclear RHA protein was partially redistributed into the cytoplasm. The short interfering RNA-mediated knockdown of RHA significantly reduced the amounts of infectious viral particles in various cells. The RHA knockdown reduced the multistep viral growth of DENV2 and Japanese encephalitis virus but not Zika virus. Further study showed that the absence of RHA resulted in a reduction of both viral RNA and protein levels, and the data obtained from the reporter replicon assay indicated that RHA does not directly promote viral protein synthesis. RHA bound to the DENV RNA and associated with three nonstructural proteins, including NS1, NS2B3, and NS4B. Further study showed that different domains of RHA mediated its interaction with these viral proteins. The expression of RHA or RHA-K417R mutant protein lacking ATPase/helicase activity in RHA-knockdown cells successfully restored DENV2 replication levels, suggesting that the helicase activity of RHA is dispensable for its proviral effect. Overall, our work reveals that RHA is an important factor of DENV and might serve as a target for antiviral agents.IMPORTANCE Dengue, caused by dengue virus, is a rapidly spreading disease, and currently there are no treatments available. Host factors involved in the viral replication of dengue virus are potential antiviral therapeutic targets. Although RHA has been shown to promote the multiplication of several viruses, such as HIV and adenovirus, its role in the flavivirus family, including dengue virus, Japanese encephalitis virus, and emerging Zika virus, remains elusive. The current study revealed that RHA relocalized into the cytoplasm upon DENV infection and associated with viral RNA and nonstructural proteins, implying that RHA was actively engaged in the viral life cycle. We further provide evidence that RHA promoted the viral yields of DENV2 independent of its helicase activity. These findings demonstrated that RHA is a new host factor required for DENV replication and might serve as a target for antiviral drugs.


Asunto(s)
Virus del Dengue/metabolismo , Virus del Dengue/fisiología , ARN Helicasas/metabolismo , Replicación Viral/fisiología , Línea Celular , Dengue/metabolismo , Dengue/virología , Virus del Dengue/enzimología , Virus del Dengue/genética , Flavivirus/genética , Humanos , Unión Proteica , ARN Helicasas/genética , ARN Viral/metabolismo , Proteínas no Estructurales Virales/metabolismo , Virus Zika/genética
7.
ACS Omega ; 3(6): 6860-6866, 2018 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-31458854

RESUMEN

Poly(lactic acid) (PLA) electrospun membranes immobilized with Zeolitic imidazole framework/graphene oxide hybrid (ZIF-8@GO) are fabricated via electrospinning. At first, ZIF-8@GO is synthesized by the in situ growth method. The UV-visible light (UV-vis) result demonstrates that ZIF-8@GO has a narrower band gap than ZIF-8. The performance of the obtained composite membrane is investigated by scanning electron microscope, Fourier transform IR spectroscopy, tensile test, water contact angle, and methylene blue (MB) removal test. The results demonstrate that the degradable PLA/ZIF-8@GO electrospun membrane shows enhanced tensile strength than neat PLA. The composite membrane also shows great MB removal ability by adsorption and photocatalytic degradation. The MB removal efficiency could reach over 90% at very low ZIF-8@GO concentration (0.06 mg/mL).

8.
J Cell Sci ; 127(Pt 11): 2471-82, 2014 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-24659800

RESUMEN

The formation of cytoplasmic stress granules and the innate immune response are two distinct cellular stress responses. Our study investigated the involvement of four innate immune proteins - retinoic-acid-inducible gene I (RIG-I, also known as DDX58), melanoma differentiation-associated gene 5 (MDA5, also known as IFIH1), IFN-ß promoter stimulator (IPS-1, also known as MAVS) and protein kinase regulated by dsRNA (PKR, also known as EIF2AK2) in the formation of stress granules. Knockdown of IPS-1 or PKR significantly decreased the formation of stress granules induced by double-stranded (ds)RNA. IPS-1 depletion markedly attenuated the phosphorylation of PKR and eIF2α that was triggered by dsRNA, and IPS-1 facilitated the in vitro autophosphorylation of PKR. In IPS-1-depleted cells, the dsRNA-mediated dimerization of PKR through its dsRNA-binding domains was significantly abrogated, suggesting that IPS-1 might be involved in PKR dimerization. By co-immunoprecipitation and pulldown assays, our data demonstrate that IPS-1 directly binds to PKR through the IPS-1 caspase activation and recruitment domain (CARD), suggesting that the effect of IPS-1 on the formation of stress granules might be exerted through interacting with PKR and mediating its activation. PKR was recruited into stress granules upon activation, whereas the majority of IPS-1 protein formed clusters on mitochondrial membranes. Our work provides the first evidence that the innate signaling molecule IPS-1 plays an essential role in stress granule formation.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Gránulos Citoplasmáticos/metabolismo , Membranas Mitocondriales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteína 58 DEAD Box , ARN Helicasas DEAD-box/genética , ARN Helicasas DEAD-box/metabolismo , Dimerización , Células HeLa , Calor/efectos adversos , Humanos , Inmunidad Innata , Helicasa Inducida por Interferón IFIH1 , Fosforilación/genética , Unión Proteica , Transporte de Proteínas , ARN Bicatenario/metabolismo , ARN Interferente Pequeño/genética , Receptores Inmunológicos , Esteroles/toxicidad , Estrés Fisiológico/genética , eIF-2 Quinasa/genética , eIF-2 Quinasa/metabolismo
9.
PLoS One ; 8(1): e55108, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23372823

RESUMEN

BACKGROUND: Dengue virus (DENV) is found in the tropical and subtropical regions and affects millions of people annually. Currently, no specific vaccine or antiviral treatment against dengue virus is available. Innate immunity has been shown to be important for host resistance to DENV infection. Although protein kinase regulated by double-stranded RNA (PKR) has been found to promote the innate signaling in response to infection by several viruses, its role in the innate response to DENV infection is still unclear. Our study aimed to investigate the role of PKR in DENV-induced innate immune responses. METHODOLOGY/PRINCIPAL FINDINGS: By RNAi, silencing of PKR significantly enhanced the expression of interferon (IFN)-ß in DENV infected human lung epithelial A549 cells. Western blot and immunofluorescence microscopy data showed that PKR knockdown upregulated the activation of innate signaling cascades including p38 and JNK mitogen-activated protein kinases (MAPKs), interferon regulatory factor-3 and NF-κB, following DENV2 infection. Likewise, a negative regulatory effect of PKR on the IFN production was also observed in poly(IC) challenged cells. Moreover, the PKR knockdown-mediated IFN induction was attenuated by RIG-I or IPS-1 silencing. Finally, overexpression of a catalytically inactive PKR mutant (K296R), but not of a mutant lacking dsRNA binding activity (K64E) or the double mutant (K64EK296R), reversed the IFN induction mediated by PKR knockdown, suggesting that the dsRNA binding activity is required for PKR to downregulate IFN production. CONCLUSIONS/SIGNIFICANCE: PKR acts as a negative regulator of IFN induction triggered by DENVs and poly(IC), and this regulation relies on its dsRNA binding activity. These findings reveal a novel regulatory role for PKR in innate immunity, suggesting that PKR might be a promising target for anti-DENV treatments.


Asunto(s)
Células Epiteliales Alveolares/metabolismo , Células Epiteliales Alveolares/virología , Virus del Dengue/fisiología , Dengue/inmunología , Dengue/metabolismo , Interferones/biosíntesis , eIF-2 Quinasa/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Células Epiteliales Alveolares/inmunología , Línea Celular , Proteína 58 DEAD Box , ARN Helicasas DEAD-box/genética , ARN Helicasas DEAD-box/metabolismo , Dengue/genética , Regulación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Células Hep G2 , Humanos , Inmunidad Innata , Factor 3 Regulador del Interferón/metabolismo , Helicasa Inducida por Interferón IFIH1 , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , FN-kappa B/metabolismo , Poli I-C/metabolismo , ARN Bicatenario/metabolismo , Receptores Inmunológicos , Replicación Viral , eIF-2 Quinasa/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
10.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 28(6): 592-5, 2012 Jun.
Artículo en Chino | MEDLINE | ID: mdl-22691350

RESUMEN

AIM: To clone and express protein kinase regulated by double-stranded RNA (PKR) gene, and to purify and isolate PKR interacting proteins. METHODS: By using specific primers, PKR gene fragments tagged with HA and FLAG (FLAG-PKR-HA, and HA-PKR-FLAG) were amplified by PCR, and cloned into pSG5 vector. The recombinant plasmids were transfected into PKR knockdown (PKR(kd);) HeLa cells by Lipfectamine(TM); 2000. The expression of tagged PKR was confirmed by Western blotting. Finally, the PKR interacting proteins were isolated by tandem affinity purification (TAP) system using HA and FLAG antibodies, and visualized by Western blotting and SDS-PAGE silver staining. RESULTS: PKR expression plasmids were constructed and TAP system was successfully established. Silver staining showed that PKR, and two potential PKR interacting protein fragments were isolated by SDS-PAGE. CONCLUSION: We have successfully purified and isolated PKR interacting proteins, thus providing a basis for future research.


Asunto(s)
eIF-2 Quinasa/genética , eIF-2 Quinasa/metabolismo , Clonación Molecular , Expresión Génica , Orden Génico , Vectores Genéticos/genética , Células HeLa , Humanos , Unión Proteica , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/aislamiento & purificación , Proteínas Recombinantes de Fusión/metabolismo , Transfección , eIF-2 Quinasa/aislamiento & purificación
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