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Search Results: 1 - 10 of 469168 matches for " Javier A Menendez "
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Metabostemness: A New Cancer Hallmark
Frontiers in Oncology , 2014, DOI: 10.3389/fonc.2014.00262
Abstract: The acquisition of and departure from stemness in cancer tissues might not only be hardwired by genetic controllers, but also by the pivotal regulatory role of the cellular metabotype, which may act as a “starter dough” for cancer stemness traits. We have coined the term metabostemness to refer to the metabolic parameters causally controlling or functionally substituting the epitranscriptional orchestration of the genetic reprogramming that redirects normal and tumor cells toward less-differentiated CSC cellular states. Certain metabotypic alterations might operate as pivotal molecular events rendering a cell of origin susceptible to epigenetic rewiring required for the acquisition of aberrant stemness and, concurrently, of refractoriness to differentiation. The metabostemness attribute can remove, diminish, or modify the nature of molecular barriers present in Waddington’s epigenetic landscapes, thus allowing differentiated cells to more easily (re)-enter into CSC cellular macrostates. Activation of the metabostemness trait can poise cells with chromatin states competent for rapid dedifferentiation while concomitantly setting the idoneous metabolic stage for later reprogramming stimuli to finish the journey from non-cancerous into tumor-initiating cells. Because only a few permitted metabotypes will be compatible with the operational properties owned by CSC cellular states, the metabostemness property provides a new framework through which to pharmacologically resolve the apparently impossible problem of discovering drugs aimed to target the molecular biology of the cancer stemness itself. We are embarking on one of the cancer field’s biggest challenges, namely the discovery of the key metabolic features and the elite metabolites that influence chromatin structure and epigenetic circuits in charge of CSC reprogramming and the incorporation of novel metaboloepigenetic strategies that can effectively hamper cancer initiation and progression at the stem cell level.
Transphosphorylation of kinase-dead HER3 and breast cancer progression: a new standpoint or an old concept revisited?
Javier A Menendez, Ruth Lupu
Breast Cancer Research , 2007, DOI: 10.1186/bcr1773
Abstract: The notion that breast cancer disease can be viewed as a biological process that is driven by overactive human epidermal growth factor receptor (HER)1/2 receptor tyrosine kinases (RTKs) has led to development of various anti-HER tyrosine kinase agents. Several of these have undergone clinical trials, including low-molecular-weight inhibitors with highly selective and reversible tyrosine kinase inhibiting properties [1-5]. Unfortunately, following much clinical and basic science research, we have learned that simple measurement of overactive HER tyrosine kinases does not predict HER TKI efficacy. Initial phase II studies [3,4] demonstrated that the HER1 tyrosine kinase inhibitor (TKI) gefitinib did not have high efficacy in heavily pretreated populations of patients with metastatic breast cancer, particularly after chemotherapy. With few exceptions, clinical studies of the HER1 TKI gefitinib in breast cancer have demonstrated poor clinical responses and a disease control rate of approximately 10%. Indeed, tumour responses induced by HER1 TKIs are infrequent and transient, with sensitive patients rapidly developing secondary resistance. Therefore, molecular criteria for predicting sensitivity to HER TKIs are needed to allow appropriate use of these agents and to facilitate planning of future research.Failure to reverse breast cancer progression despite apparent inhibition of HER1 and HER2 kinase functions in cell-based assays as well as in patient tissues and tumours is an enigma that is not yet resolved [6]. Although it is kinase defective, the HER family member HER3 can be phosphorylated by HER1 or HER2, and HER3 can couple with the pro-survival phosphatidylinositol-3-OH kinase (PI[3]K)/Akt pathway directly whereas HER1 and HER2 cannot [5] (Figure 1). Based on these findings, Sergina and coworkers [6] recently suggested that HER3, and consequently the PI(3)K/Akt pathway, evade inhibition by current HER family TKIs via a compensatory shift in the HER3 phosphorylation
Autophagy Facilitates the Development of Breast Cancer Resistance to the Anti-HER2 Monoclonal Antibody Trastuzumab
Alejandro Vazquez-Martin, Cristina Oliveras-Ferraros, Javier A. Menendez
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0006251
Abstract: Autophagy has been emerging as a novel cytoprotective mechanism to increase tumor cell survival under conditions of metabolic stress and hypoxia as well as to escape chemotherapy-induced cell death. To elucidate whether autophagy might also protect cancer cells from the growth inhibitory effects of targeted therapies, we evaluated the autophagic status of preclinical breast cancer models exhibiting auto-acquired resistance to the anti-HER2 monoclonal antibody trastuzumab (Tzb). We first examined the basal autophagic levels in Tzb-naive SKBR3 cells and in two pools of Tzb-conditioned SKBR3 cells (TzbR), which optimally grow in the presence of Tzb doses as high as 200 μg/ml Tzb. Fluorescence microscopic analyses revealed that the number of punctate LC3 structures -a hallmark of autophagy- was drastically higher in Tzb-refractory cells than in Tzb-sensitive SKBR3 parental cells. Immunoblotting analyses confirmed that the lipidation product of the autophagic conversion of LC3 was accumulated to high levels in TzbR cells. High levels of the LC3 lipidated form in Tzb-refractory cells were accompanied by decreased p62/sequestosome-1 protein expression, a phenomenon characterizing the occurrence of increased autophagic flux. Moreover, increased autophagy was actively used to survive Tzb therapy as TzbR pools were exquisitely sensitive to chemical inhibitors of autophagosomal formation/function. Knockdown of LC3 expression via siRNA similarly resulted in reduced TzbR cell proliferation and supra-additively interacted with Tzb to re-sensitize TzbR cells. Sub-groups of Tzb-naive SKBR3 parental cells accumulated LC3 punctate structures and decreased p62 expression after treatment with high-dose Tzb, likely promoting their own resistance. This is the first report showing that HER2-overexpressing breast cancer cells chronically exposed to Tzb exhibit a bona fide up-regulation of the autophagic activity that efficiently works to protect breast cancer cells from the growth-inhibitory effects of Tzb. Therapeutic targeting autophagosome formation/function might represent a novel molecular avenue to reduce the emergence of Tzb resistance in HER2-dependent breast carcinomas.
Circulating fatty acid synthase: an exploratory biomarker to predict efficacy of the dual HER1/HER2 tyrosine kinase inhibitor lapatinib
Cristina Oliveras-Ferraros, Sílvia Cufí, Tamara Sauri-Nadal, Sonia Barco, Bego?a Martin-Castillo, Alejandro Vazquez-Martin, Javier A Menendez
Breast Cancer Research , 2011, DOI: 10.1186/bcr2799
Abstract: AMP-activated protein kinase (AMPK)-activating drugs, by mimicking an elevated AMP/ATP ratio in BC cells, drastically augment the release of extracellular FASN in HER2-positive BC cells [2]. Lapatinib-induced deprivation of tumor cell energy activates AMPK to trigger an entire cascade of metabolic events, including suppression of FASN expression and activity [1,3]. We hypothesized that a differential ability to initiate AMPK-sensed metabolic stress responses may provide information about the efficacy of HER-targeting drugs via changes in the extracellular FASN status. Enzyme-linked immunosorbent assay (ELISA)-based quantitative analyses revealed that lapatinib treatment drastically enhanced extracellular FASN concentration (by at least 8.0-fold) (Figure 1a). Immunoblotting assessment of AMPK phosphorylation at Thr172 confirmed that lapatinib treatment induced a strong activation of AMPK (Figure 1b). A weak but detectable upregulation of PP-AMPKThr172 was observed upon treatment with gefitinib. Trastuzumab, cetuximab, and erlotinib - all of which are unable to promote FASN release - failed to activate AMPK. AMPK knockdown using short interfering RNA (siRNA) transfection [2] fully prevented lapatinib-induced FASN release (Figure 1). Immunoblotting and cell imaging analyses confirmed that FASN was depleted from the cytosol of lapatinib-treated HER2 overexpressors and accumulated in their extracellular milieu (Figure 1).Treatment with lapatinib dramatically increased FASN release (by approximately 17 times) in lapatinib-responsive SKBR3 TzbR cells (Figure 1c), which were selected for long-term outgrowth in trastuzumab-containing culture medium. Extracellular FASN remained unaltered in response to trastuzumab or lapatinib in JIMT-1 BC cells, which exhibit de novo cross-refractoriness to multiple HER1/2-targeted therapies (Figure 1c). Lapatinib treatment significantly activated AMPK and promoted an enormous accumulation of extracellular FASN in lapatinib-hypersensitive MC
Olive oil's bitter principle reverses acquired autoresistance to trastuzumab (Herceptin?) in HER2-overexpressing breast cancer cells
Javier A Menendez, Alejandro Vazquez-Martin, Ramon Colomer, Joan Brunet, Alegria Carrasco-Pancorbo, Rocio Garcia-Villalba, Alberto Fernandez-Gutierrez, Antonio Segura-Carretero
BMC Cancer , 2007, DOI: 10.1186/1471-2407-7-80
Abstract: Semi-preparative HPLC was used to isolate EVOO polyphenols (i.e., tyrosol, hydroxytyrosol, oleuropein). Both the anti-proliferative and the pro-apoptotic effects of EVOO phenolics were evaluated by using MTT-based quantification of metabolically viable cells and ELISA-based detection of histone-associated DNA fragments, respectively. The nature of the interaction between oleuropein aglycone and the anti-HER2 monoclonal antibody trastuzumab (Herceptin?) was mathematically evaluated by the dose-oriented isobologram technique. HER2-specific ELISAs were employed to quantitatively assess both the basal cleavage of the HER2 extracellular domain (ECD) and the expression level of total HER2. The activation status of HER2 was evaluated by immunoblotting procedures using a monoclonal antibody specifically recognizing the tyrosine phosphorylated (Phosphor-Tyr1248) form of HER2.Among EVOO polyphenols tested, oleuropein aglycone was the most potent EVOO phenolic in decreasing breast cancer cell viability. HER2 gene-amplified SKBR3 cells were ~5-times more sensitive to oleuropein aglycone than HER2-negative MCF-7 cells. Retroviral infection of the HER2 oncogene in MCF-7 cells resulted in a "SKBR3-assimilated" phenotype of hypersensitivity to oleuropein aglycone. An up to 50-fold increase in the efficacy of trastuzumab occurred in the presence of oleuropein aglycone. A preclinical model of acquired autoresistance to trastuzumab (SKBR3/Tzb100 cells) completely recovered trastuzumab sensitivity (> 1,000-fold sensitization) when co-cultured in the presence of oleuropein aglycone. Indeed, the nature of the interaction between oleuropein aglycone and trastuzumab was found to be strongly synergistic in Tzb-resistant SKBR3/Tzb100 cells. Mechanistically, oleuropein aglycone treatment significantly reduced HER2 ECD cleavage and subsequent HER2 auto-phosphorylation, while it dramatically enhanced Tzb-induced down-regulation of HER2 expression.Olive oil's bitter principle (i.e., oleuropein a
tabAnti-HER2 (erbB-2) oncogene effects of phenolic compounds directly isolated from commercial Extra-Virgin Olive Oil (EVOO)
Javier A Menendez, Alejandro Vazquez-Martin, Rocio Garcia-Villalba, Alegria Carrasco-Pancorbo, Cristina Oliveras-Ferraros, Alberto Fernandez-Gutierrez, Antonio Segura-Carretero
BMC Cancer , 2008, DOI: 10.1186/1471-2407-8-377
Abstract: Solid phase extraction followed by semi-preparative high-performance liquid chromatography (HPLC) was used to isolate phenolic fractions from commercial EVOO. Analytical capillary electrophoresis coupled to mass spectrometry was performed to check for the composition and to confirm the identity of the isolated fractions. EVOO polyphenolic fractions were tested on their tumoricidal ability against HER2-negative and HER2-positive breast cancer in vitro models using MTT, crystal violet staining, and Cell Death ELISA assays. The effects of EVOO polyphenolic fractions on the expression and activation status of HER2 oncoprotein were evaluated using HER2-specific ELISAs and immunoblotting procedures, respectively.Among the fractions mainly containing the single phenols hydroxytyrosol and tyrosol, the polyphenol acid elenolic acid, the lignans (+)-pinoresinol and 1-(+)-acetoxypinoresinol, and the secoiridoids deacetoxy oleuropein aglycone, ligstroside aglycone, and oleuropein aglycone, all the major EVOO polyphenols (i.e. secoiridoids and lignans) were found to induce strong tumoricidal effects within a micromolar range by selectively triggering high levels of apoptotic cell death in HER2-overexpressors. Small interfering RNA-induced depletion of HER2 protein and lapatinib-induced blockade of HER2 tyrosine kinase activity both significantly prevented EVOO polyphenols-induced cytotoxicity. EVOO polyphenols drastically depleted HER2 protein and reduced HER2 tyrosine autophosphorylation in a dose- and time-dependent manner. EVOO polyphenols-induced HER2 downregulation occurred regardless the molecular mechanism contributing to HER2 overexpression (i.e. naturally by gene amplification and ectopically driven by a viral promoter). Pre-treatment with the proteasome inhibitor MG132 prevented EVOO polyphenols-induced HER2 depletion.The ability of EVOO-derived polyphenols to inhibit HER2 activity by promoting the proteasomal degradation of the HER2 protein itself, together with the f
Serum HER-2 concentration is associated with insulin resistance and decreases after weight loss
José Fernández-Real, Javier A Menendez, Gema Frühbeck, José Moreno-Navarrete, Alejandro Vazquez-Martín, Wifredo Ricart
Nutrition & Metabolism , 2010, DOI: 10.1186/1743-7075-7-14
Abstract: Insulin sensitivity (minimal model) and serum HER-2 concentrations were evaluated in a cross sectional study in men (cohort 1, n = 167) and longitudinally after weight loss in obese subjects (cohort 2, n = 30).Serum HER-2 concentrations were positively associated with BMI and waist circumference (both r = 0.18, p = 0.02), post-load glucose (r = 0.28, p = 0.001) and fasting triglycerides (r = 0.26, p = 0.001); and negatively associated with insulin sensitivity (r = -0.29, p = 0.002, n = 109). Subjects with type 2 diabetes showed significantly increased soluble serum HER-2 concentrations. In different multivariate regression models, fasting triglycerides emerged as the factor that independently contributed to 10-11% of serum HER-2 variance.Serum HER-2 concentrations correlated significantly with fasting triglycerides and insulin sensitivity index in subjects from cohort 2. Weight loss led to a significant decrease of serum HER-2 concentrations. The change in serum HER-2 concentrations were significantly associated with the change in percent body fat and fasting triglycerides in young (below the median age of the cohort) subjects.Serum HER-2 concentrations might be implicated in the pathophysiology of insulin resistance and associated comorbidities.Some cancers -including those of the breast [1], colorectum [2], endometrium [3], liver [4], and pancreas [5] occur more commonly in individuals with diabetes. A recent meta-analysis of 20 studies showed that women with (versus without) diabetes had a statistically significant 20% increased risk of breast cancer (RR, 1.20; 95% CI, 1.12-1.28) [6].The mechanisms underlying the relation between type 2 diabetes and breast cancer risk may be related to alterations in circulating concentrations of insulin and insulin-like growth factors (IGFs). It is well known that insulin resistance and increased insulin secretion for long periods are characteristics of type 2 diabetes both before and after disease onset. Insulin has been demons
Genetic and environmental factors affecting some reproductive traits of Holstein cows in Cuba
A Menendez Buxadera, L Dempfle
Genetics Selection Evolution , 1997, DOI: 10.1186/1297-9686-29-4-469
La reforma procesal penal en el Perú: rompiendo moldes, conquistando metas y enfrentando pendientes
María Antonieta Delgado Menendez
Derecho PUCP , 2010,
Abstract: Alcances de la Reforma Procesal Penal.
Mammosphere Formation in Breast Carcinoma Cell Lines Depends upon Expression of E-cadherin
Juan Manuel Iglesias, Izaskun Beloqui, Francisco Garcia-Garcia, Olatz Leis, Alejandro Vazquez-Martin, Arrate Eguiara, Silvia Cufi, Andres Pavon, Javier A. Menendez, Joaquin Dopazo, Angel G. Martin
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0077281
Abstract: Tumors are heterogeneous at the cellular level where the ability to maintain tumor growth resides in discrete cell populations. Floating sphere-forming assays are broadly used to test stem cell activity in tissues, tumors and cell lines. Spheroids are originated from a small population of cells with stem cell features able to grow in suspension culture and behaving as tumorigenic in mice. We tested the ability of eleven common breast cancer cell lines representing the major breast cancer subtypes to grow as mammospheres, measuring the ability to maintain cell viability upon serial non-adherent passage. Only MCF7, T47D, BT474, MDA-MB-436 and JIMT1 were successfully propagated as long-term mammosphere cultures, measured as the increase in the number of viable cells upon serial non-adherent passages. Other cell lines tested (SKBR3, MDA-MB-231, MDA-MB-468 and MDA-MB-435) formed cell clumps that can be disaggregated mechanically, but cell viability drops dramatically on their second passage. HCC1937 and HCC1569 cells formed typical mammospheres, although they could not be propagated as long-term mammosphere cultures. All the sphere forming lines but MDA-MB-436 express E-cadherin on their surface. Knock down of E-cadherin expression in MCF-7 cells abrogated its ability to grow as mammospheres, while re-expression of E-cadherin in SKBR3 cells allow them to form mammospheres. Therefore, the mammosphere assay is suitable to reveal stem like features in breast cancer cell lines that express E-cadherin.
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