Examinando por Autor "Martínez-Useros, Javier"

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DEK is a potential marker for aggressive phenotype and irinotecan-based therapy response in metastatic colorectal cancer
(Springer-Nature, 2014-12-16) Martínez-Useros, Javier; Rodríguez-Remírez, Maria; Borrero-Palacios, Aurea; Moreno, Irene; Cebrian, Arancha; Gomez del Pulgar, Teresa; del Puerto-Nevado, Laura; Vega-Bravo, Ricardo; Puime-Otin, Alberto; Perez, Nuria; Zazo, Sandra; Senin, Clara; Fernández-Aceñero, María Jesús; Soengas, Marisol; Rojo, Federico; García-Foncillas, Jesus
Background: DEK is a transcription factor involved in stabilization of heterochromatin and cruciform structures. It plays an important role in development and progression of different types of cancer. This study aims to analyze the role of DEK in metastatic colorectal cancer. Methods: Baseline DEK expression was firstly quantified in 9 colorectal cell lines and normal mucosa by WB. SiRNA-mediated DEK inhibition was carried out for transient DEK silencing in DLD1 and SW620 to dissect its role in colorectal cancer aggressiveness. Irinotecan response assays were performed with SN38 over 24 hours and apoptosis was quantified by flow cytometry. Ex-vivo assay was carried out with 3 fresh tumour tissues taken from surgical resection and treated with SN38 for 24 hours. DEK expression was determined by immunohistochemistry in 67 formalin-fixed paraffin-embedded tumour samples from metastatic colorectal cancer patients treated with irinotecan-based therapy as first-line treatment. Results: The DEK oncogene is overexpressed in all colorectal cancer cell lines. Knock-down of DEK on DLD1 and SW620 cell lines decreased cell migration and increased irinotecan-induced apoptosis. In addition, low DEK expression level predicted irinotecan-based chemotherapy response in metastatic colorectal cancer patients with KRAS wild-type. Conclusions: These data suggest DEK overexpression as a crucial event for the emergence of an aggressive phenotype in colorectal cancer and its potential role as biomarker for irinotecan response in those patients with KRAS wild-type status.
PP2A Inhibition Is a Common Event in Colorectal Cancer and Its Restoration Using FTY720 Shows Promising Therapeutic Potential
(AACR Journals, 2014-04-01) Cristobal, Ion; Manso, Rebeca; Rincon, Raul; Carames, Cristina; Senin, Clara; Borrero, Aurea; Martínez-Useros, Javier; Rodriguez, Maria; Zazo, Sandra; Aguilera, Oscar; Madoz-Gurpide, Juan; Rojo, Federico; García-Foncillas, Jesus
Protein phosphatase 2A (PP2A) is a tumor suppressor that regulates many signaling pathways crucial for cell transformation. In fact, decreased activity of PP2A has been reported as a recurrent alteration in many types of cancer. Here, we show that PP2A is frequently inactivated in patients with colorectal cancer, indicating that PP2A represents a potential therapeutic target for this disease. We identified overexpression of the endogenous PP2A inhibitors SET and CIP2A, and downregulation of regulatory PP2A such as PPP2R2A and PPP2R5E, as contributing mechanisms to PP2A inhibition in colorectal cancer. Moreover, we observed that its restoration using FTY720 impairs proliferation and clonogenic potential of colorectal cancer cells, induces caspase-dependent apoptosis, and affects AKT and extracellular signal-regulated kinase-1/2 activation status. Interestingly, treatment with FTY720 showed an additive effect with 5- fluorouracil, SN-38, and oxaliplatin, drugs used in standard chemotherapy in patients with colorectal cancer. These results suggest that PP2A activity is commonly decreased in colorectal cancer cells, and that the use of PP2A activators, such as FTY720, might represent a potential novel therapeutic strategy in colorectal cancer. Mol Cancer Ther; 13(4); 938–47. 2014 AACR.
Vitamin D induces SIRT1 activation through K610 deacetylation in colon cancer
(eLife Sciences Publications Limited, 2023-08-02) García-Martínez, José Manuel; Chocarro-Calvo, Ana; Martínez-Useros, Javier; Fernández-Aceñero, María Jesús; Fiuza, M. Carmen; Cáceres-Rentero, Jose; De la Vieja, Antonio; Barbáchano, Antonio; Muñoz, Alberto; Larriba, María Jesús; García-Jiménez, Custodia
Posttranslational modifications of epigenetic modifiers provide a flexible and timely mechanism for rapid adaptations to the dynamic environment of cancer cells. SIRT1 is an NAD+-dependent epigenetic modifier whose activity is classically associated with healthy aging and longevity, but its function in cancer is not well understood. Here, we reveal that 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3, calcitriol), the active metabolite of vitamin D (VD), promotes SIRT1 activation through auto-deacetylation in human colon carcinoma cells, and identify lysine 610 as an essential driver of SIRT1 activity. Remarkably, our data show that the post-translational control of SIRT1 activity mediates the antiproliferative action of 1,25(OH)2D3. This effect is reproduced by the SIRT1 activator SRT1720, suggesting that SIRT1 activators may offer new therapeutic possibilities for colon cancer patients who are VD deficient or unresponsive. Moreover, this might be extrapolated to inflammation and other VD deficiency-associated and highly prevalent diseases in which SIRT1 plays a prominent role.