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1.
J Pathol ; 248(4): 501-513, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-30957234

RESUMEN

Glioblastoma (GBM) is a highly invasive brain neoplasia with an elevated recurrence rate after surgical resection. The cyclin D1 (Ccnd1)/Cdk4-retinoblastoma 1 (RB1) axis is frequently altered in GBM, leading to overproliferation by RB1 deletion or by Ccnd1-Cdk4 overactivation. High levels of Ccnd1-Cdk4 also promote GBM cell invasion by mechanisms that are not so well understood. The purpose of this work is to elucidate the in vivo role of cytoplasmic Ccnd1-Cdk4 activity in the dissemination of GBM. We show that Ccnd1 activates the invasion of primary human GBM cells through cytoplasmic RB1-independent mechanisms. By using GBM mouse models, we observed that evaded GBM cells showed cytoplasmic Ccnd1 colocalizing with regulators of cell invasion such as RalA and paxillin. Our genetic data strongly suggest that, in GBM cells, the Ccnd1-Cdk4 complex is acting upstream of those regulators. Accordingly, expression of Ccnd1 induces focal adhesion kinase, RalA and Rac1 activities. Finally, in vivo experiments demonstrated increased GBM dissemination after expression of membrane-targeted Ccnd1. We conclude that Ccnd1-Cdk4 activity promotes GBM dissemination through cytoplasmic and RB1-independent mechanisms. Therefore, inhibition of Ccnd1-Cdk4 activity may be useful to hinder the dissemination of recurrent GBM. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias Encefálicas/genética , Ciclina D1/genética , Regulación Neoplásica de la Expresión Génica , Glioblastoma/genética , Animales , Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Movimiento Celular , Ciclina D1/metabolismo , Citoplasma/metabolismo , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Masculino , Ratones , Ratones SCID , Invasividad Neoplásica
2.
J Pathol ; 247(1): 72-85, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30206933

RESUMEN

Many human cancers present Phosphatase and tensin homolog (PTEN) deficiency and between 20 and 30% of colorectal tumors show PTEN loss. The transcription factor, E2 promoter binding factor 1 (E2F-1), exhibits tumor promoter or suppressive functions depending on cellular type and tissue context, but its role in the progression and development of colorectal carcinogenesis was largely unknown. Here, using a tamoxifen-inducible PTEN knockout mouse model, we have demonstrated that loss of PTEN leads to the development of colorectal tumorigenesis through the serrated pathway. Next, we studied PTEN loss-driven colorectal lesions in the context of E2F-1 deficiency in vivo. Our results revealed that monoallelic and biallelic absence of E2F-1 led to an increased incidence and progression of serrated tumorigenesis induced by PTEN loss. Finally, we investigated the mechanisms by which double PTEN/E2F-1 deficiency leads to enhanced tumorigenesis. We found that colorectal tumors from PTEN/E2F-1 double knockout mice and the human colorectal carcinoma cell line HT29 with shRNA-mediated downregulation of PTEN and E2F-1 exhibit hyperactivation of the RAS-MAPK pathway, accumulation of DNA damage and resistance to apoptosis. To date, this is the first preclinical study evaluating the effect of genetic deletion of E2F-1 in colorectal malignancies driven by PTEN deficiency. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Asunto(s)
Carcinogénesis , Neoplasias Colorrectales/enzimología , Factor de Transcripción E2F1/metabolismo , Fosfohidrolasa PTEN/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Animales , Apoptosis , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Daño del ADN , Factor de Transcripción E2F1/genética , Regulación Neoplásica de la Expresión Génica , Células HT29 , Humanos , Ratones Noqueados , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Fosfohidrolasa PTEN/genética , Transducción de Señal , Proteínas Supresoras de Tumor/genética , Proteínas ras/metabolismo
3.
Gynecol Oncol ; 153(2): 425-435, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30853360

RESUMEN

OBJECTIVES: The PI3K/AKT/mTOR pathway is frequently overactivated in endometrial cancer (EC). We assessed the efficacy of ABTL0812, a novel first-in-class molecule presenting a unique mechanism of action inhibiting this pathway. METHODS: We investigated the effects of ABTL0812 on proliferation, cell death and modulation of intracellular signaling pathways in a wide panel of endometrioid and non-endometrioid cell lines, an inducible PTEN knock-out murine model, and two patient-derived xenograft murine models of EC. Then, TRIB3 expression was evaluated as potential ABTL0812 pharmacodynamic biomarker in a Phase 1b/2a clinical trial. RESULTS: ABTL0812 induced an upregulation of TRIB3 expression, resulting in the PI3K/AKT/mTOR axis inhibition and autophagy cell death induction on EC cells but not in healthy endometrial cells. ABTL0812 treatment also impaired PTEN knock-out cells to progress from hyperplasia to cancer. The therapeutic effects of ABTL0812 were demonstrated in vivo. ABTL0812 increased TRIB3 mRNA levels in whole blood samples of eight EC patients, demonstrating that TRIB3 mRNA could be used as a pharmacodynamic biomarker to monitor the ABTL0812 treatment. CONCLUSIONS: ABTL0812 may represent a novel and highly effective therapeutic agent by inducing TRIB3 expression and autophagy in EC patients, including those with poorer prognosis.


Asunto(s)
Antineoplásicos/farmacología , Proteínas de Ciclo Celular/metabolismo , Neoplasias Endometriales/tratamiento farmacológico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Represoras/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Anciano , Animales , Autofagia/efectos de los fármacos , Proteínas de Ciclo Celular/biosíntesis , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Neoplasias Endometriales/metabolismo , Neoplasias Endometriales/patología , Femenino , Humanos , Ratones , Persona de Mediana Edad , Proteínas Serina-Treonina Quinasas/biosíntesis , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas Represoras/biosíntesis , Proteínas Represoras/genética , Regulación hacia Arriba/efectos de los fármacos
4.
J Pathol ; 242(2): 152-164, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28349562

RESUMEN

PTEN is one of the most frequently mutated genes in human cancers. The frequency of PTEN alterations is particularly high in endometrial carcinomas. Loss of PTEN leads to dysregulation of cell division, and promotes the accumulation of cell cycle complexes such as cyclin D1-CDK4/6, which is an important feature of the tumour phenotype. Cell cycle proteins have been presented as key targets in the treatment of the pathogenesis of cancer, and several CDK inhibitors have been developed as a strategy to generate new anticancer drugs. Palbociclib (PD-332991) specifically inhibits CDK4/6, and it has been approved for use in metastatic breast cancer in combination with letrazole. Here, we used a tamoxifen-inducible Pten knockout mouse model to assess the antitumour effects of cyclin D1 knockout and CDK4/6 inhibition by palbociclib on endometrial tumours. Interestingly, both cyclin D1 deficiency and palbociclib treatment triggered shrinkage of endometrial neoplasias. In addition, palbociclib treatment significantly increased the survival of Pten-deficient mice, and, as expected, had a general effect in reducing tumour cell proliferation. To further analyse the effects of palbociclib on endometrial carcinoma, we established subcutaneous tumours with human endometrial cancer cell lines and primary endometrial cancer xenografts, which allowed us to provide more translational and predictive data. To date, this is the first preclinical study evaluating the response to CDK4/6 inhibition in endometrial malignancies driven by PTEN deficiency, and it reveals an important role of cyclin D-CDK4/6 activity in their development. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Asunto(s)
Antineoplásicos/farmacología , Ciclina D1/genética , Neoplasias Endometriales/tratamiento farmacológico , Fosfohidrolasa PTEN/genética , Piperazinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Animales , Carcinogénesis , Ciclina D1/antagonistas & inhibidores , Ciclina D1/metabolismo , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/genética , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/genética , Modelos Animales de Enfermedad , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Femenino , Humanos , Ratones , Ratones Noqueados , Tamoxifeno/efectos adversos , Trasplante Heterólogo
5.
Sci Rep ; 12(1): 14821, 2022 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-36050359

RESUMEN

The extracellular matrix and the correct establishment of epithelial cell polarity plays a critical role in epithelial cell homeostasis and cell polarity. In addition, loss of tissue structure is a hallmark of carcinogenesis. In this study, we have addressed the role of extracellular matrix in the cellular responses to TGF-ß. It is well known that TGF-ß is a double-edged sword: it acts as a tumor suppressor in normal epithelial cells, but conversely has tumor-promoting effects in tumoral cells. However, the factors that determine cellular outcome in response to TGF-ß remain controversial. Here, we have demonstrated that the lack of extracellular matrix and consequent loss of cell polarity inhibits TGF-ß-induced apoptosis, observed when endometrial epithelial cells are polarized in presence of extracellular matrix. Rather, in absence of extracellular matrix, TGF-ß-treated endometrial epithelial cells display features of epithelial-to-mesenchymal transition. We have also investigated the molecular mechanism of such a switch in cellular response. On the one hand, we found that the lack of Matrigel results in increased AKT signaling which is sufficient to inhibit TGF-ß-induced apoptosis. On the other hand, we demonstrate that TGF-ß-induced epithelial-to-mesenchymal transition requires ERK and SMAD2/3 activation. In summary, we demonstrate that loss of cell polarity changes the pro-apoptotic function of TGF-ß to tumor-associated phenotype such as epithelial-to-mesenchymal transition. These results may be important for understanding the dual role of TGF-ß in normal versus tumoral cells.


Asunto(s)
Transición Epitelial-Mesenquimal , Matriz Extracelular , Factor de Crecimiento Transformador beta , Apoptosis/efectos de los fármacos , Carcinogénesis/metabolismo , Endometrio/metabolismo , Células Epiteliales , Matriz Extracelular/metabolismo , Femenino , Humanos , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta/farmacología
6.
Cancers (Basel) ; 13(15)2021 Jul 28.
Artículo en Inglés | MEDLINE | ID: mdl-34359707

RESUMEN

EndoG influences mitochondrial DNA replication and is involved in somatic cell proliferation. Here, we investigated the effect of ENDOG/Endog expression on proliferation in different tumor models. Noteworthy, ENDOG deficiency reduced proliferation of endometrial tumor cells expressing low PTEN/high p-AKT levels, and Endog deletion blunted the growth of PTEN-deficient 3D endometrial cultures. Furthermore, ENDOG silencing reduced proliferation of follicular thyroid carcinoma and glioblastoma cell lines with high p-AKT expression. High ENDOG expression was associated with a short time to treatment in a cohort of patients with chronic lymphocytic leukemia (CLL), a B-cell lymphoid neoplasm with activation of PI3K/AKT. This clinical impact was observed in the less aggressive CLL subtype with mutated IGHV in which high ENDOG and low PTEN levels were associated with worse outcome. In summary, our results show that reducing ENDOG expression hinders growth of some tumors characterized by low PTEN activity and high p-AKT expression and that ENDOG has prognostic value for some cancer types.

7.
J Invest Dermatol ; 140(6): 1253-1265, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-31877318

RESUMEN

Melanoma is a malignant neoplasia that is highly resistant to chemotherapy and radiotherapy and is associated with poor prognosis in advanced stage. Targeting melanoma that harbors the common BRAFV600E mutation with kinase inhibitors, such as vemurafenib, reduces tumor burden, but these tumors frequently acquire resistance to these drugs. We previously proposed that T-type calcium channel (TTCC) expression may serve as a biomarker for melanoma progression and prognosis, and we showed that TTCC blockers reduce migration and invasion rates because of autophagy blockade only in BRAFV600E-mutant melanoma cells. Here, we demonstrated that high expression of the TTCC Cav3.1 isoform is related to autophagic status in vemurafenib-resistant BRAFV600E-mutant melanoma cells and human biopsies, and in silico analysis revealed an enrichment of Cav3.1 expression in post-treatment melanomas. We also demonstrated that the TTCC blocker mibefradil induces apoptosis and impairs migration and invasion via inhibition of autophagy in resistant melanoma cells and mouse xenograft models. Moreover, we identified an association between PTEN status and Cav3.1 expression in these cells as a marker of sensitivity to combination therapy in resistant cells. Together, our results suggest that TTCC blockers offer a potential targeted therapy in resistant BRAFV600E-mutant melanoma and a therapeutic strategy to reduce progression toward BRAF inhibitor resistance.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/metabolismo , Melanoma/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Neoplasias Cutáneas/tratamiento farmacológico , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bloqueadores de los Canales de Calcio/uso terapéutico , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Humanos , Melanoma/genética , Melanoma/patología , Ratones , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Vemurafenib/farmacología , Vemurafenib/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto
8.
Cell Death Differ ; 24(8): 1443-1458, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28524854

RESUMEN

The TGF-ß/Smad and the PI3K/AKT signaling pathways are important regulators of proliferation and apoptosis, and their alterations lead to cancer development. TGF-ß acts as a tumor suppressor in premalignant cells, but it is a tumor promoter for cancerous cells. Such dichotomous actions are dictated by different cellular contexts. Here, we have unveiled a PTEN-Smad3 regulatory loop that provides a new insight in the complex cross talk between TGF-ß/Smad and PI3K/AKT signaling pathways. We demonstrate that TGF-ß triggers apoptosis of wild-type polarized endometrial epithelial cells by a Smad3-dependent activation of PTEN transcription, which results in the inhibition of PI3K/AKT signaling pathway. We show that specific Smad3 knockdown or knockout reduces basal and TGF-ß-induced PTEN expression in endometrial cells, resulting in a blockade of TGF-ß-induced apoptosis and an enhancement of cell proliferation. Likewise Smad3 deletion, PTEN knockout prevents TGF-ß-induced apoptosis and increases cell proliferation by increasing PI3K/AKT/mTOR signaling. In summary, our results demonstrate that Smad3-PTEN signaling axis determine cellular responses to TGF-ß.


Asunto(s)
Endometrio/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Fosfohidrolasa PTEN/genética , Proteína smad3/genética , Factor de Crecimiento Transformador beta/farmacología , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Endometrio/citología , Endometrio/metabolismo , Células Epiteliales/citología , Células Epiteliales/metabolismo , Retroalimentación Fisiológica , Femenino , Regulación de la Expresión Génica , Ratones , Ratones Noqueados , Fosfohidrolasa PTEN/antagonistas & inhibidores , Fosfohidrolasa PTEN/deficiencia , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Transducción de Señal , Proteína smad3/antagonistas & inhibidores , Proteína smad3/deficiencia , Transcripción Genética , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo
9.
Eur J Cancer ; 63: 74-87, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27288872

RESUMEN

The phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) axis is frequently dysregulated in cancer due to mutations in different nodes of the pathway or constitutive activation of receptor tyrosine kinases. Multikinase inhibitors as sorafenib and regorafenib represent a therapeutic approach for the treatment of these types of tumours. In the present study, we have evaluated the anti-tumoural effects of Sorafenib and Regorafenib on endometrial, prostate and thyroid neoplasias. Both inhibitors reduced cell viability in vitro and lead to a disruption of the PI3K/AKT/mTOR pathway. In vivo, we have demonstrated that Sorafenib and Regorafenib reduce thyroid hyperplasias induced by the loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), although none of the treatments eliminated the disease. Altogether, we present the first study that correlates the response to multikinase inhibitors with a specific mutation. Moreover, this is the first report characterising the response to Regorafenib in thyroid, prostate and endometrial neoplasias.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma/tratamiento farmacológico , Neoplasias Endometriales/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/uso terapéutico , Neoplasias de la Tiroides/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Niacinamida/farmacología , Niacinamida/uso terapéutico , Fosfohidrolasa PTEN/deficiencia , Compuestos de Fenilurea/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Sorafenib
10.
Oncotarget ; 7(19): 26979-91, 2016 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-27105504

RESUMEN

Cyclin D1 (Ccnd1) is a proto-oncogen amplified in many different cancers and nuclear accumulation of Ccnd1 is a characteristic of tumor cells. Ccnd1 activates the transcription of a large set of genes involved in cell cycle progress and proliferation. However, Ccnd1 also targets cytoplasmic proteins involved in the regulation of cell migration and invasion. In this work, we have analyzed by immunohistochemistry the localization of Ccnd1 in endometrial, breast, prostate and colon carcinomas with different types of invasion. The number of cells displaying membranous or cytoplasmic Ccnd1 was significantly higher in peripheral cells than in inner cells in both collective and pushing invasion patterns of endometrial carcinoma, and in collective invasion pattern of colon carcinoma. Also, the cytoplasmic localization of Ccnd1 was higher when tumors infiltrated as single cells, budding or small clusters of cells. To evaluate cytoplasmic function of cyclin D1, we have built a variant (Ccnd1-CAAX) that remains attached to the cell membrane therefore sequestering this cyclin in the cytoplasm. Tumor cells harboring Ccnd1-CAAX showed high levels of invasiveness and metastatic potential compared to those containing the wild type allele of Ccnd1. However, Ccnd1-CAAX expression did not alter proliferative rates of tumor cells. We hypothesize that the role of Ccnd1 in the cytoplasm is mainly associated with the invasive capability of tumor cells. Moreover, we propose that subcellular localization of Ccnd1 is an interesting guideline to measure cancer outcome.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Ciclina D1/metabolismo , Citoplasma/metabolismo , Neoplasias/metabolismo , Secuencias de Aminoácidos/genética , Animales , Biomarcadores de Tumor/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Membrana Celular/metabolismo , Células Cultivadas , Neoplasias del Colon/metabolismo , Ciclina D1/genética , Neoplasias Endometriales/metabolismo , Femenino , Humanos , Inmunohistoquímica , Masculino , Ratones Desnudos , Ratones SCID , Microscopía Confocal , Invasividad Neoplásica , Neoplasias de la Próstata/metabolismo
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