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1.
Anticancer Res ; 40(2): 743-749, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32014916

RESUMEN

BACKGROUND/AIM: The hepatic stellate cells (HSCs) have relationship to cancer progression. The aim of this study is to investigate the effect of HSCs and the role of IL-6/Stat3 pathway on hepatocellular carcinoma (HCC) progression. MATERIALS AND METHODS: HCCs were co-cultured with HSCs. The viability and migration ability of cancer cells were detected. Epithelial-mesenchymal transition (EMT) marker (E-cadherin), stem cell marker (CD44) and p-signal transducer and activator of transcription 3 (p-STAT3) of cancer cells were evaluated. Finally, interleukin-6 (IL-6) neutralization was performed. RESULTS: Co-culture of HCCs with HSCs increased cancer cell viability and migration ability. EMT and stemness of cancer cells increased with HSCs. Following IL-6 neutralization, phospho-STAT3 activation, cancer cell viability and migration, as well as EMT, and stemness of cancer cells decreased. CONCLUSION: HSCs promoted HCC progression through the IL-6/STAT3 pathway.


Asunto(s)
Carcinoma Hepatocelular/metabolismo , Células Estrelladas Hepáticas/metabolismo , Interleucina-6/metabolismo , Neoplasias Hepáticas/metabolismo , Carcinoma Hepatocelular/patología , Comunicación Celular/fisiología , Línea Celular Tumoral , Movimiento Celular/fisiología , Supervivencia Celular/fisiología , Técnicas de Cocultivo , Células Hep G2 , Células Estrelladas Hepáticas/patología , Humanos , Neoplasias Hepáticas/patología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Factor de Transcripción STAT3/metabolismo , Transducción de Señal
2.
J Phys Chem Lett ; 11(4): 1357-1363, 2020 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-32017568

RESUMEN

Large doses of anticancer drugs entering cancer cell nuclei are found to be effective at killing cancer cells and increasing chemotherapeutic effectiveness. Here we report red-emissive carbon quantum dots, which can enter into the nuclei of not only cancer cells but also cancer stem cells. After doxorubicin was loaded at the concentration of 30 µg/mL on the surfaces of carbon quantum dots, the average cell viability of HeLa cells was decreased to only 21%, while it was decreased to 50% for free doxorubicin. The doxorubicin-loaded carbon quantum dots also exhibited a good therapeutic effect by eliminating cancer stem cells. This work provides a potential strategy for developing carbon quantum-dot-based anticancer drug carriers for effective eradication of cancers.


Asunto(s)
Carbono/química , Núcleo Celular/metabolismo , Doxorrubicina/metabolismo , Portadores de Fármacos/química , Puntos Cuánticos/química , Animales , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/química , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Células HeLa , Humanos , Ratones , Ratones Desnudos , Microscopía Confocal , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Células Madre Neoplásicas/citología , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Trasplante Heterólogo
3.
Anticancer Res ; 40(2): 795-805, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-32014922

RESUMEN

BACKGROUND/AIM: We previously have described the "3+1" tumors cure approach consisting of individual time schedule of cyclophosphamide and dsDNA preparation administrations. The aim of the study was to adapt the "3+1" approach based on eradication of cancer stem cells to the model of murine ascitic cyclophosphamide-resistant lymphosarcoma (RLS). MATERIALS AND METHODS: Adaptation of the "3+1" approach includes the identification of the timing to disrupt the tumorigenic potential of a certain tumor. RESULTS: The proposed therapeutic scheme allowed complete reduction of primary RLS ascites in experimental animals. However, reduction of primary ascites due to the complementary action of cyclophosphamide and dsDNA was inevitably followed by the development of a secondary one, most likely arising from a solid carcinomatous formation in the peritoneal wall. CONCLUSION: The "3+1" approach resulted in the elimination of cancer stem cells, and, as a consequence, in the complete reduction of RLS ascites.


Asunto(s)
Linfoma no Hodgkin/tratamiento farmacológico , Células Madre Neoplásicas/metabolismo , Animales , Linfoma no Hodgkin/patología , Ratones
4.
Life Sci ; 248: 117463, 2020 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-32097663

RESUMEN

Breast cancer is one of the well-known malignant tumors among women. In spite of attempts to classifying breast cancer according to its histological and molecular properties, it is almost considered as a dilemma in treatment. Nowadays, public and medical attentions have primary focused on foods with anti-cancer properties to alleviate the cancer problems. Flavonoid components such as Quercetin (Qu) as dietary substances with high attention of ordinary people might provide potential of alternative or complementary medicine in breast cancer. With regard to the wide range of health benefits of Qu, researchers have been generally convinced to bring Qu as natural compounds in cancer therapy. Moreover, the high cost of standard cancer treatments and the failure of most conventional treatments have led the medical community to pursue cost-effective prevention and treatment. As a result, a great deal of concentration is attracted to diet/cancer reciprocal action. Therefore, this review study has aimed to identify what has revealed the critical properties of Qu such as anti-inflammatory, anti-oxidant, and even its effect on proliferation, angiogenesis, or apoptosis that are considered as anti-tumor property to enhance breast cancer treatment.


Asunto(s)
Antiinflamatorios/uso terapéutico , Antineoplásicos Fitogénicos/uso terapéutico , Antioxidantes/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Regulación Neoplásica de la Expresión Génica , Neovascularización Patológica/tratamiento farmacológico , Quercetina/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos Clínicos como Asunto , Femenino , Humanos , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Ensayos Antitumor por Modelo de Xenoinjerto
5.
Chem Commun (Camb) ; 56(10): 1509-1512, 2020 Feb 04.
Artículo en Inglés | MEDLINE | ID: mdl-31917383

RESUMEN

Gallium(iii) complexes with polypridyl ligands are shown to kill bulk osteosarcoma cells and osteosarcoma stem cells (OSCs) with up to nanomolar potency. The most effective complex induces apoptosis in osteosarcoma cells by damaging genomic DNA. To the best of our knowledge this is the first investigation into metal-based anti-OSC agents.


Asunto(s)
Complejos de Coordinación/farmacología , Galio/química , Células Madre Neoplásicas/efectos de los fármacos , Línea Celular Tumoral , Núcleo Celular/química , Núcleo Celular/metabolismo , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/química , Complejos de Coordinación/metabolismo , Humanos , Células Madre Neoplásicas/citología , Células Madre Neoplásicas/metabolismo , Osteosarcoma/metabolismo , Osteosarcoma/patología
6.
Nat Commun ; 11(1): 562, 2020 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-31992715

RESUMEN

Cancer immunotherapy has emerged as a promising cancer treatment. However, the presence of immune-refractory tumor cells limits its clinical success by blocking amplification of anti-tumor immunity. Previously, we found that immune selection by immunotherapy drives the evolution of tumors toward multi-modal resistant and stem-like phenotypes via transcription induction of AKT co-activator TCL1A by NANOG. Here, we report a crucial role of HSP90A at the crossroads between NANOG-TCL1A axis and multi-aggressive properties of immune-edited tumor cells by identifying HSP90AA1 as a NANOG transcriptional target. Furthermore, we demonstrate that HSP90A potentiates AKT activation through TCL1A-stabilization, thereby contributing to the multi-aggressive properties in NANOGhigh tumor cells. Importantly, HSP90 inhibition sensitized immune-refractory tumor to adoptive T cell transfer as well as PD-1 blockade, and re-invigorated the immune cycle of tumor-reactive T cells. Our findings implicate that the HSP90A-TCL1A-AKT pathway ignited by NANOG is a central molecular axis and a potential target for immune-refractory tumor.


Asunto(s)
Proteínas HSP90 de Choque Térmico/efectos de los fármacos , Proteínas HSP90 de Choque Térmico/metabolismo , Inmunidad , Inmunoterapia , Células Madre Neoplásicas/inmunología , Células Madre Neoplásicas/metabolismo , Animales , Línea Celular Tumoral , Femenino , Humanos , Isoxazoles/farmacología , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones SCID , Proteína Homeótica Nanog/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Resorcinoles/farmacología
7.
Adv Exp Med Biol ; 1217: 79-98, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31898223

RESUMEN

Stem cells can remain quiescent, self-renewal, and differentiate into many types of cells and even cancer stem cells. The coordination of these complex processes maintains the homeostasis of the organism. Ubiquitination is an important posttranslational modification process that regulates protein stability and activity. The ubiquitination levels of stem cell-associated proteins are closely related with stem cell characteristics. Cullin-RING Ligases (CRLs) are the largest family of E3 ubiquitin ligases, accounting for approximately 20% of proteins degraded by proteasome. In this review, we discuss the role of CRLs in stem cell homeostasis, self-renewal, and differentiation and expound their ubiquitination substrates. In addition, we also discuss the effect of CRLs on the formation of cancer stem cells that may provide promising therapy strategies for cancer.


Asunto(s)
Proteínas Cullin/metabolismo , Células Madre/metabolismo , Animales , Humanos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Complejo de la Endopetidasa Proteasomal/metabolismo , Células Madre/citología , Ubiquitinación
8.
Chem Biol Interact ; 316: 108938, 2020 Jan 25.
Artículo en Inglés | MEDLINE | ID: mdl-31926151

RESUMEN

Eugenol a phenylpropanoid, predominantly found in clove is a very common spice in daily cuisine. It already reported to have anti-breast cancer activity. In this study, the effect of eugenol on CSC (Cancer Stem Cell) markers and its main regulator ß-catenin both in vivo Ehrlich Ascites Carcinoma (EAC) cell line and in vitro MCF-7 cell line was investigated with that of the untreated group. The therapeutic doses were found to significantly induce apoptosis leaving normal mice and cells unaffected. The in-depth analysis revealed the downregulation of ß-catenin thereby facilitating its degradation by N-terminal phosphorylation of Ser37 residue. Significant downregulation of various CSC markers was also observed in vivo after eugenol treatment those are regulated by the intracellular status of ß-catenin. These findings were validated by the effect of eugenol on the formation of the secondary sphere in vitro. Notable downregulation of the enriched stemness of secondary mammosphere was detected by the significantly decreased percentage of CD44+/CD24-/low population after eugenol treatment along with their distorted morphology and smaller the number of spheres. The underlying mechanism revealed significant downregulation of ß-catenin and the set of CSC markers along with their reduced mRNA expression in secondary sphere culture. Therefore, it can be concluded from the study that eugenol exerts its chemotherapeutic potential by impeding ß-catenin nuclear translocation thereby promoting its cytoplasmic degradation as a result stemness is being suppressed potentially even if in the enriched state. Therefore the study contributes to reduce the cancer-induced complications associated with the CSC population. This will ultimately confer the longer and improved patient's life.


Asunto(s)
Apoptosis/efectos de los fármacos , Eugenol/farmacología , Células Madre Neoplásicas/efectos de los fármacos , beta Catenina/metabolismo , Animales , Sitios de Unión , Línea Celular Tumoral , Regulación hacia Abajo , Eugenol/química , Eugenol/uso terapéutico , Femenino , Humanos , Ratones , Simulación del Acoplamiento Molecular , Neoplasias/tratamiento farmacológico , Células Madre Neoplásicas/citología , Células Madre Neoplásicas/metabolismo , Factor 3 de Transcripción de Unión a Octámeros/genética , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Fosforilación/efectos de los fármacos , Receptor Notch1/genética , Receptor Notch1/metabolismo , Trasplante Heterólogo , beta Catenina/química
9.
Anticancer Res ; 40(1): 133-141, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31892561

RESUMEN

BACKGROUND/AIM: Aberrant expression of the BMI1 oncogene has been prevalently found in a variety of human cancers, including cervical cancer. Recent studies have shown that PTC209, a specific BMI1 inhibitor, exhibits high potency in inhibiting the growth of colon, breast, oral cancer cells and cancer-initiating cells, indicative of its chemotherapeutic potential. In the current study, we evaluated the inhibitory abilities of PTC209 in cervical cancer cells. MATERIALS AND METHODS: Three cervical cell lines, C33A, HeLa, and SiHa were treated with PTC209. The impacts of PTC209 on BMI1 were investigated using quantitative reverse-transcription PCR assay (qRT-PCR) and western blotting; changes in cell viability, cell cycle distribution, and apoptosis were assessed using cell viability testing, colony formation assay and flow cytometry analyses, respectively. RESULTS: PTC209 exhibited considerably high short-term and long-term cytotoxicities in all tested cervical cancer cell lines regardless of their HPV infection status, TP53 and pRb statuses. PTC209 significantly downregulated the expression of BMI1 in cervical cancer cell lines, and such downregulation led to G0/G1 arrest (p<0.05). Moreover, PTC209 drove more cells into apoptosis (p<0.05). CONCLUSION: PTC209 (BMI1-targeting agents, in general) represents a novel chemotherapeutic agent with potential in cervical cancer therapy.


Asunto(s)
Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Complejo Represivo Polycomb 1/antagonistas & inhibidores , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular/efectos de los fármacos , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Complejo Represivo Polycomb 1/genética , Complejo Represivo Polycomb 1/metabolismo , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/patología
10.
Anticancer Res ; 40(1): 169-176, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31892565

RESUMEN

BACKGROUND/AIM: Cancer stem cells (CSCs) are considered to be one of the causes of tumor recurrence after chemotherapy. The purpose of our study was to isolate CSCs from human colorectal cancer cell (CRC) lines. MATERIALS AND METHODS: Nine CRC lines were screened based on the expression level of potential CSC markers to identify putative CSCs. Tumor formation capacity in immunodeficient mice was compared with that of their counterparts. Stemness, differentiation potency and sensitivity to 5-fluorouracil (5-FU), in vitro, were also assessed. Microarray analysis was used to characterize the features of the putative CSCs. RESULTS: COLO 201 cells were separated into two populations based on CD44 expression. CD44 positive (CD44+) cells showed significantly higher tumor formation capacity than CD44- cells in immunodeficient mice. CD44+ cells also possessed stemness properties and lower sensitivity to 5-FU in vitro. Moreover, cancer stemness and chemoresistance-related genes were highly up-regulated in CD44+ cells. CONCLUSION: CD44+ COLO 201 cells possessed the features of CSCs; therefore, the present CSC model could serve as a valuable tool to accelerate CSC research.


Asunto(s)
Receptores de Hialuranos/metabolismo , Células Madre Neoplásicas/metabolismo , Animales , Biomarcadores , Biomarcadores de Tumor , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Modelos Animales de Enfermedad , Citometría de Flujo , Fluorouracilo/farmacología , Xenoinjertos , Humanos , Receptores de Hialuranos/genética , Ratones
11.
Int J Cancer ; 146(5): 1281-1292, 2020 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-31456217

RESUMEN

Tumor-initiating cells are a subpopulation of cells that have self-renewal capacity to regenerate a tumor. Here, we identify stem cell-like chromatin features in human glioblastoma initiating cells (GICs) and link them to a loss of the repressive histone H3 lysine 9 trimethylation (H3K9me3) mark. Increasing H3K9me3 levels by histone demethylase inhibition led to cell death in GICs but not in their differentiated counterparts. The induction of apoptosis was accompanied by a loss of the activating H3 lysine 9 acetylation (H3K9ac) modification and accumulation of DNA damage and downregulation of DNA damage response genes. Upon knockdown of histone demethylases, KDM4C and KDM7A both differentiation and DNA damage were induced. Thus, the H3K9me3-H3K9ac equilibrium is crucial for GIC viability and represents a chromatin feature that can be exploited to specifically target this tumor subpopulation.


Asunto(s)
Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Glioblastoma/genética , Histona Demetilasas con Dominio de Jumonji/metabolismo , Células Madre Neoplásicas/metabolismo , Acetilación , Animales , Apoptosis/genética , Línea Celular Tumoral , Autorrenovación de las Células/genética , Cromatina/metabolismo , Metilación de ADN , Reparación del ADN/genética , Técnicas de Silenciamiento del Gen , Glioblastoma/patología , Células HEK293 , Histonas , Humanos , Histona Demetilasas con Dominio de Jumonji/genética , Lisina/metabolismo , Ratones , Regiones Promotoras Genéticas/genética , ARN Interferente Pequeño/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
12.
Cancer Sci ; 111(2): 406-417, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31785057

RESUMEN

STMN1 has been regarded as an oncogene and its upregulation is closely associated with malignant behavior and poor prognosis in multiple cancers. However, the detailed functions and underlying mechanisms of STMN1 are still largely unknown in hepatocellular carcinoma (HCC) development. Herein, we analyzed STMN1 expression and the related clinical significance in HCC by using well-established Protein Atlas, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) cancer databases. Analysis indicated that STMN1 was highly expressed in HCC and closely associated with vascular invasion, higher histological grade, advanced clinical grade and shorter survival time in HCC patients. Overexpressing and silencing STMN1 in HCC cell lines showed that STMN1 could regulate cell proliferation, migration, drug resistance, cancer stem cell properties in vitro as well as tumor growth in vivo. Further experiments showed that STMN1 mediated intricate crosstalk between HCC and hepatic stellate cells (HSC) by triggering the hepatocyte growth factor (HGF)/MET signal pathway. When HSC were cocultured with HCC cells, HSC secreted more HGF to stimulate the expression of STMN1 in HCC cells. Mutually, STMN1 upregulation in HCC cells facilitated HSC activation to acquire cancer-associated fibroblast (CAF) features. The MET inhibitor crizotinib significantly blocked this crosstalk and slowed tumor growth in vivo. In conclusion, our findings shed new insight on STMN1 function, and suggest that STMN1 may be used as a potential marker to identify patients who may benefit from MET inhibitor treatment.


Asunto(s)
Carcinoma Hepatocelular/patología , Células Estrelladas Hepáticas/citología , Neoplasias Hepáticas/patología , Transducción de Señal , Estatmina/genética , Animales , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Técnicas de Cocultivo , Resistencia a Antineoplásicos , Retroalimentación Fisiológica , Regulación Neoplásica de la Expresión Génica , Células Estrelladas Hepáticas/metabolismo , Factor de Crecimiento de Hepatocito/metabolismo , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Ratones , Clasificación del Tumor , Trasplante de Neoplasias , Células Madre Neoplásicas/metabolismo , Proteínas Proto-Oncogénicas c-met/metabolismo , Regulación hacia Arriba
13.
J Cancer Res Clin Oncol ; 146(1): 19-31, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31734836

RESUMEN

PURPOSE: Cancer stem cells (CSCs) are highly tumorigenic cell types that reside within specific areas of tumor microenvironment (TME), and are endowed with self-renewal and resistance properties. Here, we aimed to discuss mechanisms involved in hypoxia-derived CSC resistance and targeting for effective cancer therapy. RESULTS: Preferential localization within hypoxic niches would help CSCs develop adaptive mechanisms, mediated through the modification of responses to various stressors and, as a result, show a more aggressive behavior. CONCLUSION: Hypoxia, in fact, serves as a multi-tasking strategy to nurture CSCs with this adaptive capacity, complexing targeted therapies.


Asunto(s)
Hipoxia de la Célula/fisiología , Neoplasias/metabolismo , Neoplasias/patología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Animales , Plasticidad de la Célula/fisiología , Humanos , Neoplasias/terapia
14.
Int J Cancer ; 146(4): 1099-1113, 2020 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-31187490

RESUMEN

Acquired chemoresistance is a critical issue for advanced bladder cancer patients during long-term treatment. Recent studies reveal that a fraction of tumor cells with enhanced tumor-initiating potential, or cancer stem-like cells (CSCs), may particularly contribute to acquired chemoresistance and recurrence. Thus, CSC characterization will be the first step towards understanding the mechanisms underlying advanced disease. Here we generated long-term patient-derived cancer cells (PDCs) from bladder cancer patient specimens in spheroid culture, which is favorable for CSC enrichment. Pathological features of bladder cancer PDCs and PDC-dependent patient-derived xenografts (PDXs) were basically similar to those of their corresponding patients' specimens. Notably, CSC marker aldehyde dehydrogenase 1A1 (ALDH1A1), a critical enzyme that synthesizes retinoic acid (RA), was abundantly expressed in PDCs. ALDH1A1 inhibitors and shRNAs repressed both PDC proliferation and spheroid formation, whereas all-trans RA could rescue ALDH1A1 shRNA-suppressed spheroid formation. ALDH inhibitor also reduced the in vivo growth of PDC-derived xenografts. ALDH1A1 knockdown study showed that tubulin beta III (TUBB3) was one of the downregulated genes in PDCs. We identified functional RA response elements in TUBB3 promoter, whose transcriptional activities were substantially activated by RA. Clinical survival database reveals that TUBB3 expression may associate with poor prognosis in bladder cancer patients. Moreover, TUBB3 knockdown was sufficient to suppress PDC proliferation and spheroid formation. Taken together, our results indicate that ALDH1A1 and its putative downstream target TUBB3 are overexpressed in bladder cancer, and those molecules could be applied to alternative diagnostic and therapeutic options for advanced disease.


Asunto(s)
/metabolismo , Retinal-Deshidrogenasa/metabolismo , Tubulina (Proteína)/biosíntesis , Neoplasias de la Vejiga Urinaria/metabolismo , /antagonistas & inhibidores , Animales , Línea Celular Tumoral , Progresión de la Enfermedad , Regulación hacia Abajo , Células HEK293 , Xenoinjertos , Humanos , Masculino , Ratones , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Retinal-Deshidrogenasa/antagonistas & inhibidores , Retinal-Deshidrogenasa/genética , Receptor alfa de Ácido Retinoico , Transducción de Señal , Esferoides Celulares , Tretinoina , Tubulina (Proteína)/genética , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología
15.
Cell Mol Life Sci ; 77(2): 351-363, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31222373

RESUMEN

Cancer stem cells (CSC) are highly associated with poor prognosis in cancer patients. Our previous studies report that isorhapontigenin (ISO) down-regulates SOX2-mediated cyclin D1 induction and stem-like cell properties in glioma stem-like cells. The present study revealed that ISO could inhibit stem cell-like phenotypes and invasivity of human bladder cancer (BC) by specific attenuation of expression of CD44 but not SOX-2, at both the protein transcription and degradation levels. On one hand, ISO inhibited cd44 mRNA expression through decreases in Sp1 direct binding to its promoter region-binding site, resulting in attenuation of its transcription. On the other hand, ISO also down-regulated USP28 expression, which in turn reduced CD44 protein stability. Further studies showed that ISO treatment induced miR-4295, which specific bound to 3'-UTR activity of usp28 mRNA and inhibited its translation and expression, while miR-4295 induction was mediated by increased Dicer protein to enhance miR-4295 maturation upon ISO treatment. Our results provide the first evidence that ISO has a profound inhibitory effect on human BC stem cell-like phenotypes and invasivity through the mechanisms distinct from those previously noted in glioma stem-like cells.


Asunto(s)
Receptores de Hialuranos/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Estilbenos/farmacología , Regiones no Traducidas 3'/efectos de los fármacos , Sitios de Unión/efectos de los fármacos , Línea Celular Tumoral , Ciclina D1/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , MicroARNs/metabolismo , Células Madre Neoplásicas/metabolismo , Regiones Promotoras Genéticas/efectos de los fármacos , ARN Mensajero/metabolismo , Factores de Transcripción SOXB1/metabolismo , Células Madre , Transcripción Genética/efectos de los fármacos , Ubiquitina Tiolesterasa/metabolismo , Neoplasias de la Vejiga Urinaria
16.
Gene ; 730: 144299, 2020 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-31881249

RESUMEN

The function and mechanism of RNA editing proteins have been extensively studied, but its association with cellular processes and signaling pathways remained unaddressed. Here, we explored the function of RNA editing complementary protein- Apobec-1 Complementation Factor (A1CF) in the proliferation and colony formation of renal cell carcinoma (RCC) cells. Decreased A1CF expression inhibits the proliferation and colony formation of 786-O cells; and further signaling pathway screening demonstrated that A1CF increases ERK activation and DKK1 expression. Moreover, knockdown of DKK1 has similar phenotypes with A1CF deficiency in 786-O cells on cell proliferation and colony formation and ERK activation. Decreasing of DKK1 expression reduces the phosphorylation of ERK1/2 and MEK1/2 increased by A1CF overexpression; further, inhibiting of the phosphorylation of MEK1/2 by U0126 also decreases the ERK activation upregulated by A1CF overexpression. Deficiency of DKK1 or U0126 treatment suppresses the cell proliferation promoted by A1CF overexpression in 786-O cells; furthermore, U0126 treatment inhibits DKK1-increased cell proliferation in 786-O cells. Our results reveal that DKK1 mediates A1CF to activate ERK in promotion renal carcinoma cell proliferation and colony formation. For the important function of ERK signaling pathway in tumor metastasis and key position of DKK1 in Wnt signaling pathway, we associate RNA editing protein-A1CF with multiple cellular processes and signaling pathways through DKK1, and the key node of A1CF-DKK1-MEK/ERK axis is a potential targeting site for RCC therapy.


Asunto(s)
Carcinoma de Células Renales/genética , Proteínas de Unión al ARN/metabolismo , Apoptosis/genética , Carcinoma de Células Renales/metabolismo , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Sistema de Señalización de MAP Quinasas/genética , Proteína Quinasa 3 Activada por Mitógenos/genética , Células Madre Neoplásicas/metabolismo , Fosforilación , Edición de ARN/genética , Edición de ARN/fisiología , Proteínas de Unión al ARN/genética , Vía de Señalización Wnt
17.
Cancer Sci ; 111(2): 467-476, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31845453

RESUMEN

Collective invasion of cancer cells is the key process of circulating tumor cell (CTC) cluster formation, and greatly contributes to metastasis. Cancer stem-like cells (CSC) have a distinct advantage of motility for metastatic dissemination. To verify the role of CSC in the collective invasion, we performed 3D assays to investigate the collective invasion from cancer cell spheroids. The results demonstrated that CSC can significantly promote both collective and single-cell invasion. Further study showed that CSC prefer to move outside and lead the collective invasion. More interestingly, approximately 60% of the leader CSC in collective invasion co-expressed both epithelial and mesenchymal genes, while only 4% co-expressed in single invasive CSC, indicating that CSC with hybrid epithelial/mesenchymal phenotype play a key role in cancer cell collective invasion.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/patología , Invasividad Neoplásica/patología , Células Madre Neoplásicas/patología , Esferoides Celulares/patología , Animales , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Movimiento Celular , Transición Epitelial-Mesenquimal , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Células MCF-7 , Ratones , Metástasis de la Neoplasia , Trasplante de Neoplasias , Células Madre Neoplásicas/citología , Células Madre Neoplásicas/metabolismo , Esferoides Celulares/citología , Esferoides Celulares/metabolismo
18.
Int J Biochem Cell Biol ; 119: 105682, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31877386

RESUMEN

Cancer stem cell like cells (CSCs) present a challenge in the management of cancers due to their involvement in the development of resistance against various chemotherapeutic agents. Over expression of ABCG2 transporter gene is one of the factors responsible for drug resistance in CSCs, which causes efflux of therapeutic drugs from these cells. The development of inhibitors against CSCs has not achieved any significant success, till date. In this work, we have evaluated the anti-proliferative activity of curcumin (Cur) and quinacrine (QC) against CSCs using in vitro model system. Cur and QC synergistically inhibited the proliferation, migration and invasion of CSCs enriched side population (SP) cells of cigarette smoke condensate induced breast epithelial transformed (MCF-10A-Tr) generated metastatic cells. Cur + QC combination increased the DNA damage and inhibited the DNA repair pathways in SP cells. Uptake of QC increased in Cur pre-treated SP cells and this combination inhibited the ABCG2 activity by the reduction of ATP hydrolysis in cells. In vitro DNA binding reconstitution system suggests that QC specifically binds to DNA and caused DNA damage inside the cell. Decreased level of ABCG2, representative cell survival and DNA repair proteins were noted after Cur + QC treatment in SP cells. The molecular docking studies were performed to examine the binding behaviour of these drugs with ABCG2, which showed that QC (-53.99 kcal/mol) and Cur (-45.90 kcal/mol) occupy a highly overlapping interaction domain. This suggested that in Cur pre-treated cells, the Cur occupied the ligand-binding site in ABCG2, thus making the ligand binding site unavailable for the QC. This causes an increase in the intracellular concentration of QC. The results indicate that Cur + QC combination causes CSCs death by increasing the concentration of QC in the cells and thus causing the DNA damage and inhibiting the DNA repair pathways through modulating the ABCG2 activity.


Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/antagonistas & inhibidores , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Curcumina/farmacología , Daño del ADN , Reparación del ADN/efectos de los fármacos , Proteínas de Neoplasias/antagonistas & inhibidores , Células Madre Neoplásicas/efectos de los fármacos , Quinacrina/farmacología , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Curcumina/administración & dosificación , ADN de Neoplasias/genética , ADN de Neoplasias/metabolismo , Sinergismo Farmacológico , Femenino , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Quinacrina/administración & dosificación
19.
Anticancer Res ; 39(12): 6575-6583, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31810923

RESUMEN

BACKGROUND/AIM: The aim of this study was to examine whether the Wnt/ß-catenin signal activation is a cause of radioresistance in colon cancer by assessing the ß-catenin localization and its correlation with cancer stem cells (CSCs). MATERIALS AND METHODS: The nuclear levels of ß-catenin, the hallmark of Wnt activation, were analyzed in HCT116 and SW480 cells by immunohistochemistry, before and after irradiation. Further, we assessed CSC populations by staining for aldehyde dehydrogenase-1 (ALDH1) and CD44. RESULTS: ß-catenin was localized predominantly in the nucleus and plasma membrane in SW480 and HCT116 cells, respectively. Compared to HCT116 cells, SW480 cells displayed higher Wnt activation. At 24 h after irradiation, most of the DSBs in SW480 cells were repaired, but were still present in HCT116 cells. Additionally, compared to HCT116 cells, a significantly higher proportion of SW480 cells were ALDH1- and CD44-positive. CONCLUSION: Colon cancers with nuclear ß-catenin accumulation demonstrated greater radio-resistance with a higher number of CSCs.


Asunto(s)
Núcleo Celular/metabolismo , Neoplasias del Colon/metabolismo , Células Madre Neoplásicas/metabolismo , Tolerancia a Radiación , beta Catenina/metabolismo , /metabolismo , Línea Celular Tumoral , Membrana Celular/metabolismo , Células HCT116 , Humanos , Receptores de Hialuranos/metabolismo , Vía de Señalización Wnt
20.
Int J Nanomedicine ; 14: 8923-8941, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31814720

RESUMEN

Background: Cancer stem cells (CSCs) are responsible for cancer therapeutic resistance and metastasis. To date, in addition to surgery, chemotherapy, and radiotherapy, gene delivery has emerged as a potential therapeutic modality for ovarian cancer. Efficient and safe targeted gene delivery is complicated due to the tumor heterogeneity barrier. Ultrasound (US)-stimulated microbubbles (MBs) have demonstrated a method of enabling non-invasive targeted gene delivery. Purpose: The purpose of our study was to show the utility of poly(ethylene glycol)-SS-polyethylenimine-loaded microbubbles (PSP@MB) as an ultrasound theranostic and redox-responsive agent in a gene delivery system. Patients and methods: PSP nanoparticles were conjugated to the MB surface through biotin-avidin linkage, increasing the gene-loading efficiency of MB. The significant increase in the release of genes from the PSP@MB complexes was achieved upon ultrasound exposure. The positive surface charge in PSP@MB can condense the plasmid through electrostatic interactions; agarose-gel electrophoresis further confirmed the ability of PSP@MB to condense plasmids. The morphology, particle sizes and zeta potential of PSP@MB were characterized by transmission electron microscopy and dynamic light scattering. Results: Laser confocal microscopy showed that the combination of ultrasound with PSP@MB could promote the cellular uptake of plasmids. Plasmids which encode enhanced green fluorescence protein (EGFP) reporter genes or luciferase reporter genes were delivered to CSCs in vitro and to subcutaneous xenografts in vivo via the combination of ultrasound with PSP@MB. Gene transfection efficiency was evaluated by fluorescence microscopy and In Vivo Imaging Systems. This study demonstrated that the combination of ultrasound with PSP@MB can remarkably promote gene delivery to solid tumors as well as diminishing the toxicity towards normal tissues in vivo. The combination of PSP@MB and the use of ultrasound can efficiently enhance accumulation, extravasation and penetration into solid tumors. Conclusion: Taken together, our study showed that this novel PSP@MB and ultrasound-mediated gene delivery system could efficiently target CSCs.


Asunto(s)
Técnicas de Transferencia de Gen , Microburbujas , Polietilenglicoles/química , Polietileneimina/química , Animales , Línea Celular Tumoral , ADN/metabolismo , Femenino , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Nanopartículas/química , Nanopartículas/ultraestructura , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Neoplasias Ováricas/diagnóstico por imagen , Neoplasias Ováricas/patología , Plásmidos/metabolismo , Ultrasonografía , Ensayos Antitumor por Modelo de Xenoinjerto
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