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1.
J Am Coll Surg ; 239(4): 363-374, 2024 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-38752618

RESUMEN

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) for rectal cancer can lead to structural changes in collagen in the tumor microenvironment and increase the risk of postoperative anastomotic stenosis (AS). However, the quantitative relationship between AS and collagen has not been defined. This study is to quantitatively analyze the collagen features in rectal cancer and explore the relationship between the changes of collagen and postoperative anastomotic stenosis after nCRT. STUDY DESIGN: This is a retrospective study. A total of 371 patients with rectal cancer were included. Collagen features in the resection margin of rectal cancer anastomosis was extracted by multiphoton imaging. The least absolute shrinkage operator logistic regression was performed to select features related to AS and the collagen score (CS) was constructed. Area under the receiver operating curve (AUROC) and decision curve analysis were performed to evaluate the discrimination and clinical benefit of the nomogram. RESULTS: The probability of AS was 23% in the training cohort and 15.9% in the validation cohort. In the training cohort, the distance between tumor and resection margin, anastomotic leakage and CS were independent risk factors for postoperative AS in univariate and multivariate analyses. A nomogram was constructed based on these results. The prediction nomogram showed good discrimination (AUROC 0.864; 95% CI 0.776 to 0.952) and was validated in the validation cohort (AUROC 0.918; 95% CI 0.851 to 0.985). CONCLUSIONS: CS is an independent risk factor for AS in rectal cancer after nCRT. The predictive model based on CS can predict the occurrence of postoperative AS.


Asunto(s)
Anastomosis Quirúrgica , Colágeno , Márgenes de Escisión , Terapia Neoadyuvante , Neoplasias del Recto , Humanos , Neoplasias del Recto/terapia , Neoplasias del Recto/patología , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Anastomosis Quirúrgica/efectos adversos , Constricción Patológica/etiología , Colágeno/metabolismo , Anciano , Nomogramas , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/epidemiología , Adulto , Factores de Riesgo , Quimioradioterapia Adyuvante , Recto/cirugía , Recto/patología
2.
Prostate ; 84(9): 877-887, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38605532

RESUMEN

BACKGROUND: Prostate cancer (PCa) is the second-leading cause of cancer mortalities in the United States and is the most commonly diagnosed malignancy in men. While androgen deprivation therapy (ADT) is the first-line treatment option to initial responses, most PCa patients invariably develop castration-resistant PCa (CRPC). Therefore, novel and effective treatment strategies are needed. The goal of this study was to evaluate the anticancer effects of the combination of two small molecule inhibitors, SZL-P1-41 (SKP2 inhibitor) and PBIT (KDM5B inhibitor), on PCa suppression and to delineate the underlying molecular mechanisms. METHODS: Human CRPC cell lines, C4-2B and PC3 cells, were treated with small molecular inhibitors alone or in combination, to assess effects on cell proliferation, migration, senescence, and apoptosis. RESULTS: SKP2 and KDM5B showed an inverse regulation at the translational level in PCa cells. Cells deficient in SKP2 showed an increase in KDM5B protein level, compared to that in cells expressing SKP2. By contrast, cells deficient in KDM5B showed an increase in SKP2 protein level, compared to that in cells with KDM5B intact. The stability of SKP2 protein was prolonged in KDM5B depleted cells as measured by cycloheximide chase assay. Cells deficient in KDM5B were more vulnerable to SKP2 inhibition, showing a twofold greater reduction in proliferation compared to cells with KDM5B intact (p < 0.05). More importantly, combined inhibition of KDM5B and SKP2 significantly decreased proliferation and migration of PCa cells as compared to untreated controls (p < 0.005). Mechanistically, combined inhibition of KDM5B and SKP2 in PCa cells abrogated AKT activation, resulting in an induction of both cellular senescence and apoptosis, which was measured via Western blot analysis and senescence-associated ß-galactosidase (SA-ß-Gal) staining. CONCLUSIONS: Combined inhibition of KDM5B and SKP2 was more effective at inhibiting proliferation and migration of CRPC cells, and this regimen would be an ideal therapeutic approach of controlling CRPC malignancy.


Asunto(s)
Apoptosis , Senescencia Celular , Histona Demetilasas con Dominio de Jumonji , Neoplasias de la Próstata Resistentes a la Castración , Proteínas Proto-Oncogénicas c-akt , Proteínas Quinasas Asociadas a Fase-S , Transducción de Señal , Humanos , Proteínas Quinasas Asociadas a Fase-S/metabolismo , Proteínas Quinasas Asociadas a Fase-S/antagonistas & inhibidores , Proteínas Quinasas Asociadas a Fase-S/genética , Masculino , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Histona Demetilasas con Dominio de Jumonji/metabolismo , Histona Demetilasas con Dominio de Jumonji/antagonistas & inhibidores , Histona Demetilasas con Dominio de Jumonji/genética , Senescencia Celular/efectos de los fármacos , Senescencia Celular/fisiología , Transducción de Señal/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Progresión de la Enfermedad , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Movimiento Celular/efectos de los fármacos , Células PC-3 , Proteínas Nucleares , Proteínas Represoras
3.
Exp Cell Res ; 437(1): 113991, 2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38462208

RESUMEN

The compound 2-4(4-methylphenyl)-1,2-benzisothiazol-3(2H)-one (PBIT) is an inhibitor of the KDM5 family of lysine-specific histone demethylases that has been suggested as a lead compound for cancer therapy. The goal of this study was to explore the effects of PBIT within human prostate cancers. Micromolar concentrations of PBIT altered proliferation of castration-sensitive LNCaP and castration-resistant C4-2B, LNCaP-MDV3100 and PC-3 human prostate cancer cell lines. We then characterized the mechanism underlying the anti-proliferative effects of PBIT within the C4-2B and PC-3 cell lines. Data from Cell Death ELISAs suggest that PBIT does not induce apoptosis within C4-2B or PC-3 cells. However, PBIT did increase the amount of senescence associated beta-galactosidase. PBIT also altered cell cycle progression and increased protein levels of the cell cycle protein p21. PC-3 and C4-2B cells express varying amounts of KDM5A, KDM5B, and KDM5C, the therapeutic targets of PBIT. siRNA-mediated knockdown studies suggest that inhibition of multiple KDM5 isoforms contribute to the anti-proliferative effect of PBIT. Furthermore, combination treatments involving PBIT and the PPARγ agonist 15-deoxy-Δ-12, 14 -prostaglandin J2 (15d-PGJ2) also reduced PC-3 cell proliferation. Together, these data strongly suggest that PBIT significantly reduces the proliferation of prostate cancers via a mechanism that involves cell cycle arrest and senescence.


Asunto(s)
Neoplasias de la Próstata Resistentes a la Castración , Masculino , Humanos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Proliferación Celular , Línea Celular Tumoral , Puntos de Control del Ciclo Celular , Apoptosis , Ciclo Celular , Proteína 2 de Unión a Retinoblastoma/metabolismo
4.
J Org Chem ; 88(20): 14719-14727, 2023 Oct 20.
Artículo en Inglés | MEDLINE | ID: mdl-37792094

RESUMEN

An efficient palladium-catalyzed enantioselective direct N-alkylation of indoles using a novel type of axially chiral styrene-phosphine ligand SJTU-PHOS-1 was developed. This reaction demonstrated good functional group compatibility and a wide range scope of substrates in mild conditions. Moreover, the DFT calculations expounded the coordination mode of the metal catalyst and the axially chiral styrene-phosphine ligand in the enantioselectivity control.

5.
Genes (Basel) ; 14(9)2023 09 17.
Artículo en Inglés | MEDLINE | ID: mdl-37761952

RESUMEN

The Hessian fly (HF) is an invasive insect that has caused millions of dollars in yield losses to southeastern US wheat farms. Genetic resistance is the most sustainable solution to control HF. However, emerging biotypes are quickly overcoming resistance genes in the southeast; therefore, identifying novel sources of resistance is critical. The resistant line "UGA 111729" and susceptible variety "AGS 2038" were crossbred to generate a population of 225 recombinant inbred lines. This population was phenotyped in the growth chamber (GC) during 2019 and 2021 and in field (F) trials in Georgia during the 2021-2022 growing seasons. Visual scoring was utilized in GC studies. The percentage of infested tillers and number of pupae/larvae per tiller, and infested tiller per sample were measured in studies from 2021 to 2022. Averaging across all traits, a major QTL on chromosome 3D explained 42.27% (GC) and 10.43% (F) phenotypic variance within 9.86 centimorgans (cM). SNP marker IWB65911 was associated with the quantitative trait locus (QTL) peak with logarithm of odds (LOD) values of 14.98 (F) and 62.22 (GC). IWB65911 colocalized with resistance gene H32. KASP marker validation verified that UGA 111729 and KS89WGRC06 express H32. IWB65911 may be used for marker-assisted selection.


Asunto(s)
Sitios de Carácter Cuantitativo , Triticum , Animales , Triticum/genética , Estaciones del Año , Granjas , Hibridación Genética
6.
Mol Oncol ; 17(10): 2126-2146, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37491794

RESUMEN

Changes in FOXA1 (forkhead box protein A1) protein levels are well associated with prostate cancer (PCa) progression. Unfortunately, direct targeting of FOXA1 in progressive PCa remains challenging due to variations in FOXA1 protein levels, increased FOXA1 mutations at different stages of PCa, and elusive post-translational FOXA1 regulating mechanisms. Here, we show that SKP2 (S-phase kinase-associated protein 2) catalyzes K6- and K29-linked polyubiquitination of FOXA1 for lysosomal-dependent degradation. Our data indicate increased SKP2:FOXA1 protein ratios in stage IV human PCa compared to stages I-III, together with a strong inverse correlation (r = -0.9659) between SKP2 and FOXA1 levels, suggesting that SKP2-FOXA1 protein interactions play a significant role in PCa progression. Prostate tumors of Pten/Trp53 mice displayed increased Skp2-Foxa1-Pcna signaling and colocalization, whereas disruption of the Skp2-Foxa1 interplay in Pten/Trp53/Skp2 triple-null mice demonstrated decreased Pcna levels and increased expression of Foxa1 and luminal positive cells. Treatment of xenograft mice with the SKP2 inhibitor SZL P1-41 decreased tumor proliferation, SKP2:FOXA1 ratios, and colocalization. Thus, our results highlight the significance of the SKP2-FOXA1 interplay on the luminal lineage in PCa and the potential of therapeutically targeting FOXA1 through SKP2 to improve PCa control.


Asunto(s)
Neoplasias de la Próstata , Animales , Humanos , Masculino , Ratones , Factor Nuclear 3-alfa del Hepatocito/genética , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Lisosomas/metabolismo , Ratones Noqueados , Antígeno Nuclear de Célula en Proliferación/genética , Antígeno Nuclear de Célula en Proliferación/metabolismo , Neoplasias de la Próstata/patología , Ubiquitinación
7.
BMC Plant Biol ; 23(1): 337, 2023 Jun 24.
Artículo en Inglés | MEDLINE | ID: mdl-37353755

RESUMEN

Soil salinization is a growing issue that limits agriculture globally. Understanding the mechanism underlying salt tolerance in halophytic grasses can provide new insights into engineering plant salinity tolerance in glycophytic plants. Seashore paspalum (Paspalum vaginatum Sw.) is a halophytic turfgrass and genomic model system for salt tolerance research in cereals and other grasses. However, the salt tolerance mechanism of this grass largely unknown. To explore the correlation between Na+ accumulation and salt tolerance in different tissues, we utilized two P. vaginatum accessions that exhibit contrasting tolerance to salinity. To accomplish this, we employed various analytical techniques including ICP-MS-based ion analysis, lipidomic profiling analysis, enzyme assays, and integrated transcriptomic and metabolomic analysis. Under high salinity, salt-tolerant P. vaginatum plants exhibited better growth and Na+ uptake compared to salt-sensitive plants. Salt-tolerant plants accumulated heightened Na+ accumulation in their roots, leading to increased production of root-sourced H2O2, which in turn activated the antioxidant systems. In salt-tolerant plants, metabolome profiling revealed tissue-specific metabolic changes, with increased amino acids, phenolic acids, and polyols in roots, and increased amino acids, flavonoids, and alkaloids in leaves. High salinity induced lipidome adaptation in roots, enhancing lipid metabolism in salt-tolerant plants. Moreover, through integrated analysis, the importance of amino acid metabolism in conferring salt tolerance was highlighted. This study significantly enhances our current understanding of salt-tolerant mechanisms in halophyte grass, thereby offering valuable insights for breeding and genetically engineering salt tolerance in glycophytic plants.


Asunto(s)
Paspalum , Paspalum/genética , Tolerancia a la Sal/genética , Plantas Tolerantes a la Sal/genética , Plantas Tolerantes a la Sal/metabolismo , Antioxidantes/metabolismo , Metabolismo de los Lípidos , Peróxido de Hidrógeno/metabolismo , Fitomejoramiento , Aminoácidos/metabolismo , Salinidad
8.
Transl Res ; 252: 91-98, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36108910

RESUMEN

As depicted in the translational research continuum, dissemination of research findings to past research participants and the community-at-large is integral to improving health outcomes. Blocks in translation exist in which poor dissemination is a major contributor. Limited progress has been made on how to engage basic scientists at T1 and T2 phases to meaningfully disseminate study findings to community. Our objective is to report on 4 cases of community engaged research dissemination activities among 3 basic scientists (ie, a cancer biologist, a biochemist, and a molecular biologist.): a townhall, a radio listening session, a community newsletter, and a Facebook Live segment. The Meharry Community Engagement Core dissemination team designed these activities using community informed processes. To plan and conduct these activities, a basic scientist is partnered with a community engaged researcher and a community-based organization to create a dissemination product which can be understood and potentially used by past research participants and the community-at-large. We share reflections from basic scientists, community organizations, and event participants. Finally, we provide competencies, informed by basic scientists, needed to engage in effective, community-engaged research dissemination. The activities, reflections, and competencies can be used by basic scientists and academic institutions as models to guide their community engaged research dissemination activities. This work supports the goal to bridge the translational research gap.


Asunto(s)
Neoplasias , Investigación Biomédica Traslacional , Humanos
9.
Int J Mol Sci ; 23(7)2022 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-35409390

RESUMEN

The present studies were conducted to evaluate key serum proteins and other components that mediate anchorage-independent growth (3-D growth) of LNCaP prostate cancer cells as spheroids. The cells were cultured on ultra-low attachment plates in the absence and presence of fetuin-A and with or without extracellular vesicles. The data show that fetuin-A (alpha 2HS glycoprotein) is the serum protein that mediates 3-D growth in these cells. It does so by sequestering extracellular vesicles of various sizes on the surfaces of rounded cells that grow as spheroids. These vesicles in turn transmit growth signals such as the activation of AKT and MAP kinases in a pattern that differs from the activation of these key growth signaling pathways in adherent and spread cells growing in 2-D. In the process of orchestrating the movement and disposition of extracellular vesicles on these cells, fetuin-A is readily internalized in adhered and spread cells but remains on the surfaces of non-adherent cells. Taken together, our studies suggest the presence of distinct signaling domains or scaffolding platforms on the surfaces of prostate tumor cells growing in 3-D compared to 2-D.


Asunto(s)
Vesículas Extracelulares , Neoplasias de la Próstata , Vesículas Extracelulares/metabolismo , Humanos , Masculino , Neoplasias de la Próstata/metabolismo , Transducción de Señal , alfa-2-Glicoproteína-HS/metabolismo , alfa-Fetoproteínas/metabolismo
10.
Cancer Lett ; 525: 46-54, 2022 01 28.
Artículo en Inglés | MEDLINE | ID: mdl-34610416

RESUMEN

Sterol regulatory element-binding protein 1 (SREBP-1), a master transcription factor in lipogenesis and lipid metabolism, is critical for disease progression and associated with poor outcomes in prostate cancer (PCa) patients. However, the mechanism of SREBP-1 regulation in PCa remains elusive. Here, we report that SREBP-1 is transcriptionally regulated by microRNA-21 (miR-21) in vitro in cultured cells and in vivo in mouse models. We observed aberrant upregulation of SREBP-1, fatty acid synthase (FASN) and acetyl-CoA carboxylase (ACC) in Pten/Trp53 double-null mouse embryonic fibroblasts (MEFs) and Pten/Trp53 double-null mutant mice. Strikingly, miR-21 loss significantly reduced cell proliferation and suppressed the prostate tumorigenesis of Pten/Trp53 mutant mice. Mechanistically, miR-21 inactivation decreased the levels of SREBP-1, FASN, and ACC in human PCa cells through downregulation of insulin receptor substrate 1 (IRS1)-mediated transcription and induction of cellular senescence. Conversely, miR-21 overexpression increased cell proliferation and migration; as well as the levels of IRS1, SREBP-1, FASN, and ACC in human PCa cells. Our findings reveal that miR-21 promotes PCa progression by activating the IRS1/SREBP-1 axis, and targeting miR-21/SREBP-1 signaling pathway can be a novel strategy for controlling PCa malignancy.


Asunto(s)
Proteínas Sustrato del Receptor de Insulina/genética , MicroARNs/genética , Neoplasias de la Próstata/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Acetil-CoA Carboxilasa/genética , Animales , Proliferación Celular/genética , Progresión de la Enfermedad , Acido Graso Sintasa Tipo I/genética , Regulación Neoplásica de la Expresión Génica/genética , Xenoinjertos , Humanos , Masculino , Ratones , Neoplasias de la Próstata/patología , Transducción de Señal
11.
Transl Oncol ; 14(12): 101218, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34509951

RESUMEN

BACKGROUND: It remains under-investigated whether prostatic lipid profiles are associated with pathogenesis, progression, racial disparity, and discovery of biomarkers in prostate cancer (PCa). METHODS: The electrospray ionization-tandem mass spectrometry was applied to quantitate prostatic lipids in human and mouse PCa and non-cancer prostatic tissues. Biostatistics and bioinformatics were used to compare the concentrations of prostatic lipids at levels of total lipid, group, class and individual species between PCa and benign prostatic tissues, between races, and among pathological conditions of PCa. RESULTS: Prostatic concentrations of total lipids as well as neutral lipids were significantly higher in PCa than in benign prostatic tissues in all population and Caucasian American population, but not in African American population. The prostatic phospholipid were not statistically different between PCa and benign prostatic tissues in all study populations. Cholesteryl ester is the only lipid class significantly higher in PCa than in benign prostatic tissues in all study populations. A panel of prostatic lipid parameters in each study population was identified as diagnostic and prognostic biomarkers with >60% of sensitivity, specificity and accuracy simultaneously. Lipid profiling on mouse prostatic tissues further confirmed correlation of prostatic lipid profiles to the pathogenesis and progression of PCa. In addition, a few prostatic lipids in mouse can serve as prognostic biomarkers in differentiation of indolent from aggressive PCa. CONCLUSION: The prostatic lipids are widely associated with the pathogenesis, progression and racial disparity of PCa. A panel of prostatic lipids can serve as diagnostic, prognostic and race-specific biomarkers for PCa.

12.
Plant Genome ; 13(3): e20061, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-33169935

RESUMEN

Soft red winter wheat (SRWW) cultivar AGS 2038 has a high level of seedling and adult plant leaf rust (LR) resistance. To map and characterize LR resistance in AGS 2038, a recombinant inbred line (RIL) population consisting of 225 lines was developed from a cross between AGS 2038 and moderately resistant line UGA 111729. The parents and RIL population were phenotyped for LR response in three field environments at Plains and Griffin, GA, in the 2017-2018 and 2018-2019 growing seasons, one greenhouse environment at the adult-plant stage, and at seedling stage. The RIL population was genotyped with the Illumina iSelect 90K SNP marker array, and a total of 7667 polymorphic markers representing 1513 unique loci were used to construct a linkage map. Quantitative trait loci (QTL) analysis detected six QTL, QLr.ags-1AL, QLr.ags-2AS, QLr.ags-2BS1, QLr.ags-2BS2, QLr.ags-2BS3, and QLr.ags-2DS, for seedling and adult plant LR resistance. Of these, the major adult plant leaf rust resistance QTL, QLr.ags-1AL, was detected on all field and greenhouse adult plant tests and explained up to 34.45% of the phenotypic variation. QLr.ags-1AL, tightly flanked by IWB20487 and IWA4022 markers, was contributed by AGS 2038. Molecular marker analysis using a diagnostic marker linked to Lr59 showed that QLr.ags-1AL was different from Lr59, the only known LR resistance gene on 1AL. Therefore, the QTL was temporarily designated as Lr2K38. Lr2K38-linked marker IWB20487 was highly polymorphic among 30 SRWW lines and should be useful for selecting the Lr2K38 in wheat breeding programs.


Asunto(s)
Resistencia a la Enfermedad , Triticum , Cromosomas , Resistencia a la Enfermedad/genética , Humanos , Fitomejoramiento , Enfermedades de las Plantas/genética , Hojas de la Planta , Triticum/genética
13.
Cancer Res ; 80(21): 4633-4643, 2020 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-32868382

RESUMEN

KDM5B (lysine[K]-specific demethylase 5B) is frequently upregulated in various human cancers including prostate cancer. KDM5B controls H3K4me3/2 levels and regulates gene transcription and cell differentiation, yet the contributions of KDM5B to prostate cancer tumorigenesis remain unknown. In this study, we investigated the functional role of KDM5B in epigenetic dysregulation and prostate cancer progression in cultured cells and in mouse models of prostate epithelium-specific mutant Pten/Kdm5b. Kdm5b deficiency resulted in a significant delay in the onset of prostate cancer in Pten-null mice, whereas Kdm5b loss alone caused no morphologic abnormalities in mouse prostates. At 6 months of age, the prostate weight of Pten/Kdm5b mice was reduced by up to 70% compared with that of Pten mice. Pathologic analysis revealed Pten/Kdm5b mice displayed mild morphologic changes with hyperplasia in prostates, whereas age-matched Pten littermates developed high-grade prostatic intraepithelial neoplasia and prostate cancer. Mechanistically, KDM5B governed PI3K/AKT signaling in prostate cancer in vitro and in vivo. KDM5B directly bound the PIK3CA promoter, and KDM5B knockout resulted in a significant reduction of P110α and PIP3 levels and subsequent decrease in proliferation of human prostate cancer cells. Conversely, KDM5B overexpression resulted in increased PI3K/AKT signaling. Loss of Kdm5b abrogated the hyperactivation of AKT signaling by decreasing P110α/P85 levels in Pten/Kdm5b mice. Taken together, our findings reveal that KDM5B acts as a key regulator of PI3K/AKT signaling; they also support the concept that targeting KDM5B is a novel and effective therapeutic strategy against prostate cancer. SIGNIFICANCE: This study demonstrates that levels of histone modification enzyme KDM5B determine hyperactivation of PI3K/AKT signaling in prostate cancer and that targeting KDM5B could be a novel strategy against prostate cancer.


Asunto(s)
Carcinogénesis/metabolismo , Histona Demetilasas con Dominio de Jumonji/metabolismo , Proteínas Nucleares/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Neoplasias de la Próstata/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Represoras/metabolismo , Animales , Carcinogénesis/patología , Línea Celular Tumoral , Proteínas de Unión al ADN/metabolismo , Humanos , Masculino , Ratones , Ratones Noqueados , Neoplasias de la Próstata/metabolismo , Transducción de Señal/fisiología
15.
Am J Clin Exp Urol ; 7(4): 249-261, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31511831

RESUMEN

Interleukin-17 (IL-17) has been demonstrated to promote development of a variety of cancers including prostate cancer in genetically modified mouse models. IL-17 is the main product secreted by T helper 17 (Th17) cells. A recent study has shown that Th17 cells and related genes are upregulated in human prostate cancers. However, there is no direct experimental evidence to demonstrate Th17's role in prostate cancer. In the present study, we co-implanted mouse prostate cancer MPC3-luc cells with Th17-polarized mouse splenocytes in the prostate of immunocompetent C57BL/6J male mice. We found that Th17-polarized splenocytes promoted orthotopic allograft prostate tumor growth compared to the control splenocytes. The numbers of IL-17-positive lymphocytes and macrophages were higher in the prostate tumors grown from co-implantation of MPC3-luc cells and Th17-polarized splenocytes, compared to the prostate tumors grown from co-implantation of MPC3-luc cells and control splenocytes. Our findings provide the first direct experimental evidence that Th17 cells may promote prostate cancer growth.

16.
J Exp Clin Cancer Res ; 38(1): 43, 2019 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-30700325

RESUMEN

BACKGROUND: Some membrane proteins can translocate into the nucleus, defined as nuclear localized membrane proteins (NLMPs), including receptor tyrosine kinases (RTKs). We previously showed that nuclear MET (nMET), a member of RTKs, mediates cancer stem-like cells self-renewal to promote cancer recurrence. However, it is unknown that nMET or mMET, which is the ancestor in the evolution of cancer cell survival and clearance. Here, we aim to study the NLMP functions in cell death, differentiation and survival. METHOD: We applied the systematic reanalysis of functional NLMP and clinical investigations of nMET from databases. In addition, we used soft agar assay, immunoblotting, flow cytometry, and immunofluorescence confocal microscopy for examinations of nMET functions including stem-like cell formation, cell signaling, cell cycle regulation, and co-localization with regulators of cell signaling. ShRNA, antibody of recognizing surface membrane MET based treatment were used to downregulate endogenous nMET to uncover its function. RESULTS: We predicted and demonstrated that nMET and nEGFR are most likely not ancestors. nMET overexpression induces both cell death and survival with drug resistance and stem cell-like characters. Moreover, the paradoxical function of nMET in both cell death and cell survival is explained by the fact that nMET induces stem cell-like cell growth, DNA damage repair, to evade the drug sensitization for survival of single cells while non-stem cell-like nMET expressing single cells may undergo clearance by cell death through cell cycle arrest induced by p21. CONCLUSION: Taken together, our data suggest a link between nuclear RTK and cancer cell evolutionary clearance via cell death, and drug resistance for survival through stemness selection. Targeting evolved nuclear RTKs in cancer stem cells would be a novel avenue for precision cancer therapy.


Asunto(s)
Núcleo Celular/metabolismo , Resistencia a Antineoplásicos , Neoplasias/metabolismo , Neoplasias/patología , Células Madre Neoplásicas/patología , Proteínas Proto-Oncogénicas c-met/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Apoptosis , Núcleo Celular/genética , Proliferación Celular , Humanos , Neoplasias/genética , Células Madre Neoplásicas/metabolismo , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Tirosina Quinasas Receptoras/genética , Transducción de Señal , Células Tumorales Cultivadas
17.
Oncogene ; 38(16): 2967-2983, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30568225

RESUMEN

Nuclear receptor tyrosine kinases (nRTKs) are aberrantly upregulated in many types of cancers, but the regulation of nRTK remains unclear. We previously showed androgen deprivation therapy (ADT) induces nMET in castration-resistant prostate cancer (CRPC) specimens. Through gene expression microarray profiles reanalysis, we identified that nMET signaling requires ARF for CRPC growth in Pten/Trp53 conditional knockout mouse model. Accordingly, aberrant MET/nMET elevation correlates with ARF in human prostate cancer (PCa) specimens. Mechanistically, ARF elevates nMET through binding to MET cytoplasmic domain to stabilize MET. Furthermore, carbon nanodots resensitize cancer cells to MET inhibitors through DNA damage response. The inhibition of phosphorylation by carbon nanodots was identified through binding to phosphate group of phospho-tyrosine via computational calculation and experimental assay. Thus, nMET is essential to precision therapy of MET inhibitor. Our findings reveal for the first time that targeting nMET axis by carbon nanodots can be a novel avenue for overcoming drug resistance in cancers especially prostate cancer.


Asunto(s)
Carbono/farmacología , Núcleo Celular/efectos de los fármacos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-met/metabolismo , Tirosina/metabolismo , Antagonistas de Andrógenos/farmacología , Andrógenos/metabolismo , Animales , Línea Celular Tumoral , Núcleo Celular/metabolismo , Humanos , Masculino , Ratones , Ratones Noqueados , Fosfohidrolasa PTEN/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Transducción de Señal/efectos de los fármacos
18.
Am J Clin Exp Urol ; 6(3): 114-122, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30038943

RESUMEN

Metastasis of prostate cancer causes substantial morbidity and mortality. The role of chronic inflammatory factors in promoting the development of prostate cancer metastasis remains unexamined due to a lack of immunocompetent animal models. Here we report an orthotopic mouse allograft model of prostate cancer that was used to assess interleukin-17's role in prostate cancer metastasis. A luciferase gene was stably introduced into a mouse prostate cancer cell line MPC3, named as MPC3-luc. MPC3-luc cells were mixed with Matrigel™ and inoculated into C57BL/6 mouse prostates, with recombinant mouse interleukin-17 (IL-17) (treatment group) or without IL-17 (control group). Bioluminescent imaging was used to track the growth and metastasis of prostate cancer metastasis. Immunohistochemistry was performed to confirm metastasis. Mice in the IL-17 treatment group had significantly higher incidence of metastasis than mice in the control group. However, there was no detectable difference in primary prostate tumor growth. Metastases were confirmed as originating from prostate cancer through staining for luciferase protein expression. Our findings suggest that interleukin-17 promotes prostate cancer metastasis in an orthotopic mouse allograft model.

19.
J Org Chem ; 83(15): 8457-8463, 2018 08 03.
Artículo en Inglés | MEDLINE | ID: mdl-29905071

RESUMEN

A Cu-mediated stereoselective [4+2] annulation between N-hydroxybenzimidoyl cyanides and norbornene (NBE) has been developed for the synthesis of 4 H-1,2-oxazin-4-ones. The reaction proceeds through sequentially forming C-O/C-C bonds. The advantage of this reaction includes high stereoselectivity, excellent yields, as well as simple and mild reaction conditions. A total of 26 examples are presented along with some control experiments.

20.
Nat Commun ; 9(1): 101, 2018 01 09.
Artículo en Inglés | MEDLINE | ID: mdl-29317652

RESUMEN

Sirtuins are NAD+-dependent deacetylases that facilitate cellular stress response. They include SirT6, which protects genome stability and regulates metabolic homeostasis through gene silencing, and whose loss induces an accelerated aging phenotype directly linked to hyperactivation of the NF-κB pathway. Here we show that SirT6 binds to the H3K9me3-specific histone methyltransferase Suv39h1 and induces monoubiquitination of conserved cysteines in the PRE-SET domain of Suv39h1. Following activation of NF-κB signaling Suv39h1 is released from the IκBα locus, subsequently repressing the NF-κB pathway. We propose that SirT6 attenuates the NF-κB pathway through IκBα upregulation via cysteine monoubiquitination and chromatin eviction of Suv39h1. We suggest a mechanism based on SirT6-mediated enhancement of a negative feedback loop that restricts the NF-κB pathway.


Asunto(s)
Cisteína/metabolismo , Metiltransferasas/metabolismo , FN-kappa B/metabolismo , Dominios PR-SET , Proteínas Represoras/metabolismo , Sirtuinas/metabolismo , Animales , Línea Celular Tumoral , Células Cultivadas , Cromatina/metabolismo , Cisteína/genética , Células HCT116 , Células HEK293 , Células HeLa , Humanos , Metiltransferasas/genética , Ratones , Inhibidor NF-kappaB alfa/metabolismo , Células 3T3 NIH , Unión Proteica , Proteínas Represoras/genética , Transducción de Señal , Sirtuinas/genética , Ubiquitinación , Regulación hacia Arriba
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