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1.
Gastric Cancer ; 24(3): 624-639, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33515163

RESUMEN

BACKGROUND: Gastric cancer (GC) is the third leading cause of cancer mortality globally and a molecularly heterogeneous disease. Identifying the driver pathways in GC progression is crucial to improving the clinical outcome. Recent studies identified ASPM (abnormal spindle-like microcephaly-associated) and FOXM1 (Forkhead box protein M1) as novel Wnt and cancer stem cell (CSC) regulators; their pathogenetic roles and potential crosstalks in GC remain unclarified. METHODS: The expression patterns of ASPM isoforms and FOXM1 were profiled in normal gastric epithelial and GC tissues. The functional roles of ASPM and FOXM1 in Wnt activity, cancer stemness and GC progression, and the underlying signaling processes were investigated. RESULTS: Approximately one third of GC cells upregulate the expression of ASPM isoform I (ASPMiI) in their cytoplasm; the tumors with a high ASPMiI positive score (≥ 10%) are associated with a poor prognosis of the patients. Mechanistically, the molecular interplay among FOXM1, ASPMiI and DVL3 was found to converge on ß-catenin to control the Wnt activity and the stemness property of GC cells. This multi-mode Wnt-regulatory module serves to reinforce Wnt signals in CSCs by transcriptional regulation (FOXM1-ASPM), protein-protein interactions (ASPMiI-DVL3-ß-catenin), and nuclear translocation (FOXM1-ß-catenin). CONCLUSIONS: This study illuminates a novel Wnt- and stemness-regulatory mechanism in GC cells and identifies a novel subset of FOXM1highASPMiIhigh GC with potential to guide Wnt- and stemness-related diagnostics and therapies.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Neoplasias Gástricas/genética , Línea Celular Tumoral , China , Proteína Forkhead Box M1/metabolismo , Humanos , Proteínas del Tejido Nervioso/metabolismo , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Análisis de Supervivencia , Vía de Señalización Wnt
2.
J Pathol ; 249(4): 498-508, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31465125

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and treatment-resistant malignancy. The lack of pathway-informed biomarkers hampers the development of rational diagnostics or therapies. Recently, the protein abnormal spindle-like microcephaly-associated (ASPM) was identified as a novel Wnt and stemness regulator in PDAC, while the pathogenic roles of its protein isoforms remain unclarified. We developed novel isoform-specific antibodies and genetic knockdown (KD) of putative ASPM isoforms, whereby we uncovered that the levels of ASPM isoform 1 (iI) and ASPM-iII are variably upregulated in PDAC cells. ASPM isoforms show remarkably different subcellular locations; specifically, ASPM-iI is exclusively localized to the cortical cytoplasm of PDAC cells, while ASPM-iII is predominantly expressed in cell nuclei. Mechanistically, ASPM-iI co-localizes with disheveled-2 and active ß-catenin as well as the stemness marker aldehyde dehydrogenase-1 (ALDH-1), and its expression is indispensable for the Wnt activity, stemness, and the tumorigenicity of PDAC cells. By contrast, ASPM-iII selectively regulates the expression level of cyclin E and cell cycle progression in PDAC cells. The expression of ASPM-iI and ASPM-iII displays considerable intratumoral heterogeneity in PDAC tissues and only that of ASPM-iI was prognostically significant; it outperformed ALDH-1 staining and clinico-pathological variables in a multivariant analysis. Collectively, the distinct expression patterns and biological functions of ASPM isoforms may illuminate novel molecular mechanisms and prognosticators in PDAC and may pave the way for the development of therapies targeting this novel oncoprotein. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Asunto(s)
Carcinoma Ductal Pancreático/metabolismo , Ciclo Celular , Proliferación Celular , Células Madre Neoplásicas/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neoplasias Pancreáticas/metabolismo , Vía de Señalización Wnt , Familia de Aldehído Deshidrogenasa 1/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/secundario , Línea Celular Tumoral , Ciclina E/metabolismo , Proteínas Dishevelled/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Células Madre Neoplásicas/patología , Proteínas del Tejido Nervioso/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Isoformas de Proteínas , beta Catenina/metabolismo
3.
Int J Med Sci ; 14(9): 885-890, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28824326

RESUMEN

Lewis antigens related to the ABO blood group are fucosylated oligosaccharides and are synthesized by specific glycosyltransferases (FUTs). FUTs are involved in various biological processes including cell adhesion and tumor progression. The fucosyltransferase-2 gene (FUT2) encodes alpha (1,2) fucosyltransferase, which is responsible for the addition of the alpha (1,2)-linkage of fucose to glycans. Aberrant fucosylation occurs frequently during the development and progression of hepatocellular carcinoma (HCC). However, the association of FUT2 polymorphisms with HCC development has not been studied. Therefore, we aimed to investigate the association of FUT2 polymorphisms with demographic, etiological, and clinical characteristics and with susceptibility to HCC. In this study, a total of 339 patients and 720 controls were recruited. The genotypes of FUT2 at four single-nucleotide polymorphisms (SNPs; rs281377, rs1047781, rs601338, and rs602662) were detected by real-time polymerase chain reaction from these samples. Compared with the wild-type genotype at SNP rs1047781, which is homozygous for nucleotides AA, at least one polymorphic T allele (AT or TT) displayed significant association with clinical stage (p = 0.048) and tumor size (p = 0.022). Our study strongly implicates the polymorphic locus rs1047781 of FUT2 as being associated with HCC development.


Asunto(s)
Carcinoma Hepatocelular/genética , Fucosiltransferasas/genética , Predisposición Genética a la Enfermedad , Neoplasias Hepáticas/genética , Adulto , Alelos , Carcinoma Hepatocelular/patología , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Factores de Riesgo , Galactósido 2-alfa-L-Fucosiltransferasa
5.
Cancer Res ; 83(6): 830-844, 2023 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-36638332

RESUMEN

Small cell lung cancer (SCLC) is among the most aggressive and lethal human malignancies. Most patients with SCLC who initially respond to chemotherapy develop disease relapse. Therefore, there is a pressing need to identify novel driver mechanisms of SCLC progression to unlock treatment strategies to improve patient prognosis. SCLC cells comprise subsets of cells possessing progenitor or stem cell properties, while the underlying regulatory pathways remain elusive. Here, we identified the isoform 1 of the neurogenesis-associated protein ASPM (ASPM-I1) as a prominently upregulated stemness-associated gene during the self-renewal of SCLC cells. The expression of ASPM-I1 was found to be upregulated in SCLC cells and tissues, correlated with poor patient prognosis, and indispensable for SCLC stemness and tumorigenesis. A reporter array screening identified multiple developmental signaling pathways, including Hedgehog (Hh) and Wnt pathways, whose activity in SCLC cells depended upon ASPM-I1 expression. Mechanistically, ASPM-I1 stabilized the Hh transcriptional factor GLI1 at the protein level through a unique exon-18-encoded region by competing with the E3 ligases ß-TrCP and CUL3. In parallel, ASPM-I1 sustains the transcription of the Hh pathway transmembrane regulator SMO through the Wnt-DVL3-ß-catenin signaling axis. Functional studies verified that the ASPM-I1-regulated Hh and Wnt activities significantly contributed to SCLC aggressiveness in vivo. Consistently, the expression of ASPM-I1 positively correlated with GLI1 and stemness markers in SCLC tissues. This study illuminates an ASPM-I1-mediated regulatory module that drives tumor stemness and progression in SCLC, providing an exploitable diagnostic and therapeutic target. SIGNIFICANCE: ASPM promotes SCLC stemness and aggressiveness by stabilizing the expression of GLI1, DVL3, and SMO, representing a novel regulatory hub of Hh and Wnt signaling and targetable vulnerability.


Asunto(s)
Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Vía de Señalización Wnt , Carcinoma Pulmonar de Células Pequeñas/genética , Proteínas Hedgehog/metabolismo , Proteína con Dedos de Zinc GLI1/genética , Proteína con Dedos de Zinc GLI1/metabolismo , Línea Celular Tumoral , Recurrencia Local de Neoplasia/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Regulación Neoplásica de la Expresión Génica
6.
J Nat Prod ; 75(4): 630-5, 2012 Apr 27.
Artículo en Inglés | MEDLINE | ID: mdl-22360613

RESUMEN

Breast cancer cells express ABCG2 transporters, which mediate multidrug resistance. Discovering a novel compound that can suppress ABCG2 expression and restore drug sensitivity could be the key to improving breast cancer therapeutics. In the current work, one new nor-neolignan, asperjinone (1), as well as 12 other known compounds, was isolated from Aspergillus terreus. The structure of the new isolate was determined by spectroscopic methods. Among these isolates, terrein (2) displayed strong cytotoxicity against breast cancer MCF-7 cells. Treatment with terrein (2) significantly suppressed growth of ABCG2-expressing breast cancer cells. This suppressive effect was achieved by inducing apoptosis via activating the caspase-7 pathway and inhibiting the Akt signaling pathway, which led to a decrease in ABCG2-expressing cells and a reduction in the side-population phenotype.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/efectos de los fármacos , Antineoplásicos/aislamiento & purificación , Antineoplásicos/farmacología , Aspergillus/química , Ciclopentanos/farmacología , Lignanos/aislamiento & purificación , Lignanos/farmacología , Proteínas de Neoplasias/efectos de los fármacos , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Antineoplásicos/química , Neoplasias de la Mama/metabolismo , Caspasa 7/genética , Caspasa 7/metabolismo , Ciclopentanos/química , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Lignanos/química , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Proteínas Proto-Oncogénicas c-akt/efectos de los fármacos , Taiwán
7.
Nat Cancer ; 3(6): 734-752, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35618935

RESUMEN

Resistance to antitumor treatment contributes to patient mortality. Functional proteomic screening of organoids derived from chemotherapy-treated patients with breast cancer identified nuclear receptor corepressor 2 (NCOR2) histone deacetylase as an inhibitor of cytotoxic stress response and antitumor immunity. High NCOR2 in the tumors of patients with breast cancer predicted chemotherapy refractoriness, tumor recurrence and poor prognosis. Molecular studies revealed that NCOR2 inhibits antitumor treatment by regulating histone deacetylase 3 (HDAC3) to repress interferon regulatory factor 1 (IRF-1)-dependent gene expression and interferon (IFN) signaling. Reducing NCOR2 or impeding its epigenetic activity by modifying its interaction with HDAC3 enhanced chemotherapy responsiveness and restored antitumor immunity. An adeno-associated viral NCOR2-HDAC3 competitor potentiated chemotherapy and immune checkpoint therapy in culture and in vivo by permitting transcription of IRF-1-regulated proapoptosis and inflammatory genes to increase IFN-γ signaling. The findings illustrate the utility of patient-derived organoids for drug discovery and suggest that targeting stress and inflammatory-repressor complexes such as NCOR2-HDAC3 could overcome treatment resistance and improve the outcome of patients with cancer.


Asunto(s)
Antineoplásicos , Neoplasias de la Mama , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Detección Precoz del Cáncer , Femenino , Humanos , Recurrencia Local de Neoplasia , Co-Represor 2 de Receptor Nuclear/genética , Organoides/metabolismo , Proteómica
9.
Front Oncol ; 11: 638311, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34136381

RESUMEN

INTRODUCTION: Stem-like cancer cells or cancer stem cells (CSCs) may comprise a phenotypically and functionally heterogeneous subset of cells, whereas the molecular markers reflecting this CSC hierarchy remain elusive. The glycolytic enzyme alpha-enolase (ENO1) present on the surface of malignant tumor cells has been identified as a metastasis-promoting factor through its function of activating plasminogen. The expression pattern of surface ENO1 (sENO1) concerning cell-to-cell or CSC heterogeneity and its functional roles await further investigation. METHODS: The cell-to-cell expression heterogeneity of sENO1 was profiled in malignant cells from different types of cancers using flow cytometry. The subcellular localization of sENO1 and its functional roles in the invadopodia formation and cancer cell invasiveness were investigated using a series of imaging, molecular, and in vitro and in vivo functional studies. RESULTS: We showed here that ENO1 is specifically localized to the invadopodial surface of a significant subset (11.1%-63.9%) of CSCs in human gastric and prostate adenocarcinomas. sENO1+ CSCs have stronger mesenchymal properties than their sENO1- counterparts. The subsequent functional studies confirmed the remarkable pro-invasive and pro-metastatic capacities of sENO1+ CSCs. Mechanistically, inhibiting the surface localization of ENO1 by downregulating caveolin-1 expression compromised invadopodia biogenesis, proteolysis, and CSC invasiveness. CONCLUSIONS: Our study identified the specific expression of ENO1 on the invadopodial surface of a subset of highly invasive and pro-metastatic CSCs. sENO1 may provide a diagnostically and/or therapeutically exploitable target to improve the outcome of patients with aggressive and metastatic cancers.

10.
Stem Cell Reports ; 14(3): 462-477, 2020 03 10.
Artículo en Inglés | MEDLINE | ID: mdl-32160521

RESUMEN

Various populations of cancer stem cells (CSCs) have been identified in hepatocellular carcinoma (HCC). Wnt signaling is variably activated in HCC and regulates CSCs and tumorigenesis. We explored cell-to-cell Wnt and stemness heterogeneity in HCC by labeling freshly isolated cancer cells with a Wnt-specific reporter, thereby identifying a small subset (0.4%-8.9%) of Wnt-activityhigh cells. Further cellular subset analysis identified a refined subset of Wnt-activityhighALDH1+EpCAM+ triple-positive (TP) cells as the most stem-like, phenotypically plastic, and tumorigenic among all putative CSC populations. These TP "superpotent CSCs" (spCSCs) specifically upregulate the expression of dishevelled 1 (DVL1) through the antagonism between abnormal spindle-like microcephaly-associated (ASPM) and the ubiquitin ligase complex Cullin-3/KLHL-12. Subsequent functional and molecular studies revealed the role of DVL1 in controlling spCSCs and their tumorigenic potential. These findings provide the mechanistic basis of the Wnt and stemness heterogeneity in HCC and highlight the important role of DVL1high spCSCs in tumor progression.


Asunto(s)
Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Progresión de la Enfermedad , Proteínas Dishevelled/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Células Madre Neoplásicas/metabolismo , Vía de Señalización Wnt , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Biomarcadores de Tumor/metabolismo , Carcinogénesis/metabolismo , Carcinogénesis/patología , Proteínas Cullin/metabolismo , Epistasis Genética , Pruebas Genéticas , Proteínas Fluorescentes Verdes/metabolismo , Células Hep G2 , Humanos , Proteínas del Tejido Nervioso/metabolismo , Fenotipo , Pronóstico
11.
Chemistry ; 15(43): 11573-80, 2009 Nov 02.
Artículo en Inglés | MEDLINE | ID: mdl-19768713

RESUMEN

Six photosensitive polyketides, malbranpyrroles A-F, were discovered from the thermophilic fungus Malbranchea sulfurea by using intact-cell desorption/ionization on silicon mass (ICD-MS) and LC-SPE-NMR. These two strategies facilitate the searching and structural determination of unstable natural products. The ICD-MS indicated that only brown hyphae of M. sulfurea can produce malbranpyrroles. The biosynthetic pathway of malbranpyrroles was evidenced by 13C isotope precursors and amino acid feeding experiments. The cytotoxicity data revealed that the conformation of the conjugated system in malbranpyrroles does not affect cytotoxic potency against cancer cell lines. In addition, the chlorine atom was shown to be the pharmacophore for cytotoxicity.


Asunto(s)
Productos Biológicos/química , Cromatografía Líquida de Alta Presión , Hongos/química , Macrólidos/química , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Pirroles/química , Extracción en Fase Sólida , Productos Biológicos/toxicidad , Línea Celular Tumoral , Humanos , Macrólidos/toxicidad , Conformación Molecular , Pirroles/toxicidad
12.
J Nat Prod ; 72(7): 1273-8, 2009 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-19583252

RESUMEN

Eight new prenylated flavonoids, ugonins M-T (1-8), together with five known compounds, ugonins J-L (9-11), 5,4'-dihydroxy-4'',4''-dimethyl-5''-methyl-5''H-dihydrofurano[2'',3'':6,7]flavanone, and quercetin, were isolated and purified from the rhizomes of Helminthostachys zeylanica. The structures of the new isolates were elucidated by spectroscopic and chemical methods. Compounds 1, 3, 5, 7, 8, and 11 showed inhibition of superoxide anion generation and elastase release by human neutrophils in response to formyl-l-methionyl-l-leucyl-l-phenylalanine/cytochalasin B (FMLP/CB).


Asunto(s)
Antiinflamatorios no Esteroideos/aislamiento & purificación , Antiinflamatorios no Esteroideos/farmacología , Flavonoides/aislamiento & purificación , Flavonoides/farmacología , Neutrófilos/efectos de los fármacos , Antiinflamatorios no Esteroideos/química , Citocalasina B/farmacología , Helechos/química , Flavonoides/química , Humanos , Estructura Molecular , N-Formilmetionina Leucil-Fenilalanina/farmacología , Rizoma/química , Taiwán
13.
Cells ; 8(4)2019 03 30.
Artículo en Inglés | MEDLINE | ID: mdl-30935014

RESUMEN

Patients receiving docetaxel developed a drug resistance within a few months. We generated docetaxel-resistant PC/DX25 and DU/DX50 CRPC cells from PC-3 and DU-145 PCa cells, respectively. We investigated the mechanism behind why PC/DX25 and DU/DX50 cells exhibited higher migration and invasion ability. Transwell assays were used to measure the migration and invasion of PCa cell. Fluorescence activated cell sorter (FACS) analysis was used to determine the population of cancer stem cell (CSC)-like cell. Micro-Western Array (MWA) was used to study the changes of the protein profile. FACS analysis revealed that PC/DX25 cells and DU/DX50 cells contain higher CD44+ population. MWA and Western blotting assay revealed that protein expression of CD44, YAP, CYR61, CTGF, phospho-ERK1/2 T202/Y204, ERK and vimentin was elevated in PC/DX25 cells. Knockdown of CD44 or YAP suppressed migration and invasion of PC/DX25 and DU/DX50 cells. Knockdown of CD44 decreased expression of YAP, CTGF and CYR61 but increased phosphorylation of S127 on YAP. CD44 knockdown also suppressed protein level of AKT, phospho-AKT T308, phospho-ERK1/2 T202/Y204 and vimentin. CD44 promotes migration and invasion of docetaxel-resistant PCa cells probably via induction of Hippo-Yap signaling pathway and CD44/YAP pathway may be a therapeutic target for docetaxel-resistant PCa.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Movimiento Celular , Docetaxel/uso terapéutico , Receptores de Hialuranos/metabolismo , Fosfoproteínas/metabolismo , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Vía de Señalización Hippo , Humanos , Masculino , Invasividad Neoplásica , Proteínas de Neoplasias/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Factores de Transcripción , Cicatrización de Heridas/efectos de los fármacos , Proteínas Señalizadoras YAP
14.
Oncogene ; 38(8): 1340-1353, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30266990

RESUMEN

Recurrent and hormone-refractory prostate cancer (PCA) exhibits aggressive behaviors while current therapeutic approaches show little effect of prolonging the survival of patients with PCA. Thus, a deeper understanding of the patho-molecular mechanisms underlying the disease progression in PCA is crucial to identify novel diagnostic and/or therapeutic targets to improve the outcome of patients. Recent evidence suggests that activation of Wnt signaling in cancer stem cells (CSCs) contributes to cancer progression in malignant tumors. Here, we report that a novel Wnt co-activator ASPM (abnormal spindle-like microcephaly associated) maintains the prostate CSC subpopulation by augmenting the Wnt-ß-catenin signaling in PCA. ASPM expression is incrementally upregulated in primary and metastatic PCA, implicating its potential role in PCA progression. Consistently, downregulation of ASPM expression pronouncedly attenuated the proliferation, colony formation, and the invasive behavior of PCA cells, and dramatically reduced the number of ALDH+ CSCs and inhibited cancer stemness and tumorigenicity. Mechanistically, ASPM interacts with disheveled-3 (Dvl-3), a cardinal upstream regulator of canonical Wnt signaling, and inhibits its proteasome-dependent degradation, thereby increasing its protein stability and enabling the Wnt-induced ß-catenin transcriptional activity in PCA cells. In keeping with the role of ASPM as a CSC-regulator, ASPM co-localizes with ALDH in PCA tissues and its expression exhibits high intra-tumoral heterogeneity. The proportion of high-ASPM-expressing cells in the tumor inversely correlates with the relapse-free survival of PCA patients. Collectively, our data points to ASPM as a novel oncoprotein and an essential regulator of Wnt signaling and cancer stemness in PCA, which has important clinical and therapeutic significance.


Asunto(s)
Proliferación Celular/genética , Proteínas Dishevelled/genética , Proteínas del Tejido Nervioso/genética , Neoplasias de la Próstata/genética , Animales , Línea Celular Tumoral , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ratones , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Neoplasias de la Próstata/patología , Vía de Señalización Wnt/genética , Ensayos Antitumor por Modelo de Xenoinjerto , beta Catenina/genética
15.
Oncogene ; 38(8): 1354, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30390070

RESUMEN

In the published version of this paper the author Shu-Pin Huang's surname was incorrectly given as Hwang instead of Huang. This has now been corrected in the HTML and PDF versions of the paper.

17.
Oncotarget ; 8(5): 7691-7709, 2017 Jan 31.
Artículo en Inglés | MEDLINE | ID: mdl-28032597

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive type of pancreatic cancer with clinical characteristics of local invasion and early metastasis. Recent cohort studies indicate high fructose intake is associated with an increase in pancreatic cancer risk. However, the mechanisms by which fructose promotes pancreatic tumorigenesis remain unclear. Herein, Kras+/LSLG12D mice were crossed with Elas-CreER transgenic mice to determine whether fructose intake directly contributes to tumor formation. Orthotopic tumor-xenograft experiments were performed to determine whether fructose substitution enhances the metastatic potential of PDAC cells. The mechanisms underlying the effects of fructose were explored by RNAseq analysis in combination with high-performance anion exchange chromatography. Dietary fructose was initially found to promote the development of aggressive pancreatic cancer in mice conditionally expressing KrasG12D in the adult pancreas. We further revealed that fructose substitution enhanced the metastatic potential of human PDAC cell via selective outgrowth of aggressive ABCG2-positive subpopulations and elevating N-acetylmannosamine levels that upregulated ß-galactoside α2,6-sialyltransferase 1 (ST6Gal1), thereby promoting distant metastasis. Finally, we observed that PDAC patients expressing higher levels of ST6Gal1 and GLUT5 presented poorer prognosis compared to other groups. In conclusion, our findings have elucidated a crucial role of ST6Gal1 in regulating the invasiveness of PDACs in a fructose-responsive manner.


Asunto(s)
Antígenos CD/metabolismo , Carcinoma Ductal Pancreático/enzimología , Movimiento Celular/efectos de los fármacos , Azúcares de la Dieta/toxicidad , Fructosa/toxicidad , Neoplasias Pancreáticas/enzimología , Sialiltransferasas/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Anciano , Animales , Antígenos CD/genética , Antineoplásicos/farmacología , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/secundario , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Femenino , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Genes ras , Transportador de Glucosa de Tipo 5/metabolismo , Hexosaminas/metabolismo , Humanos , Estimación de Kaplan-Meier , Masculino , Ratones Endogámicos NOD , Ratones SCID , Ratones Transgénicos , Persona de Mediana Edad , Invasividad Neoplásica , Proteínas de Neoplasias/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Pronóstico , Interferencia de ARN , Sialiltransferasas/genética , Factores de Tiempo , Transfección , Regulación hacia Arriba
19.
J Exp Med ; 213(13): 2967-2988, 2016 12 12.
Artículo en Inglés | MEDLINE | ID: mdl-27881732

RESUMEN

Although traditional chemotherapy kills a fraction of tumor cells, it also activates the stroma and can promote the growth and survival of residual cancer cells to foster tumor recurrence and metastasis. Accordingly, overcoming the host response induced by chemotherapy could substantially improve therapeutic outcome and patient survival. In this study, resistance to treatment and metastasis has been attributed to expansion of stem-like tumor-initiating cells (TICs). Molecular analysis of the tumor stroma in neoadjuvant chemotherapy-treated human desmoplastic cancers and orthotopic tumor xenografts revealed that traditional maximum-tolerated dose chemotherapy, regardless of the agents used, induces persistent STAT-1 and NF-κB activity in carcinoma-associated fibroblasts. This induction results in the expression and secretion of ELR motif-positive (ELR+) chemokines, which signal through CXCR-2 on carcinoma cells to trigger their phenotypic conversion into TICs and promote their invasive behaviors, leading to paradoxical tumor aggression after therapy. In contrast, the same overall dose administered as a low-dose metronomic chemotherapy regimen largely prevented therapy-induced stromal ELR+ chemokine paracrine signaling, thus enhancing treatment response and extending survival of mice carrying desmoplastic cancers. These experiments illustrate the importance of stroma in cancer therapy and how its impact on treatment resistance could be tempered by altering the dosing schedule of systemic chemotherapy.


Asunto(s)
Administración Metronómica , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , FN-kappa B/metabolismo , Receptores de Interleucina-8B/metabolismo , Factor de Transcripción STAT1/metabolismo , Neoplasias de la Mama/patología , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Humanos , Células MCF-7 , Células del Estroma/metabolismo , Células del Estroma/patología , Células U937
20.
Org Lett ; 17(10): 2330-3, 2015 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-25915447

RESUMEN

Two novel meroterpenoids, yaminterritrems A (1) and B (2), were isolated from Aspergillus terreus collected from hot spring zones in Yang-Ming Mountain, Taiwan, and cultured at 40 °C. The structures of 1 and 2 were elucidated by NMR, MS spectral and X-ray crystallographic analyses. The biosynthetic route for 1 and 2 involving the conversion of the sesquiterpene with phenyl-α-pyrone is proposed. Besides, 2 exhibited a dose-dependent inhibitory effect on COX-2 expression in LPS-stimulated RAW264.7 macrophages.


Asunto(s)
Aspergillus/química , Inhibidores de la Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa 2/metabolismo , Pironas/química , Sesquiterpenos/química , Sesterterpenos/biosíntesis , Sesterterpenos/química , Cristalografía por Rayos X , Lipopolisacáridos/farmacología , Macrófagos/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Estructura Molecular , Taiwán
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