RESUMEN
BACKGROUND: AMP-activated protein kinase (AMPK) has a central role in cellular energy sensing and is activated in preclinical tumour models following anti-vascular endothelial growth factor (VEGF) therapy. The possible predictive or prognostic role of AMPK status in cancer patients treated with anti-VEGF drugs has not been investigated so far. METHODS: Expression of components of the AMPK pathway including phosphorylated AMPK (pAMPK), phosphorylated acetyl-Coa carboxylase (pACC) and liver kinase B1 (LKB1) was investigated by immunohistochemistry in 48 colorectal cancers treated with FOLFIRI plus bevacizumab. Correlation between pAMPK and pACC and associations between the AMPK pathway scores and clinico-pathological characteristics were assessed. Overall survival (OS) was estimated through Kaplan-Meier method, whereas hazard ratios were computed to identify prognostic factors. RESULTS: Fourteen patients (29.2%) were included in the pAMPK-negative group (score ≤5), whereas 34 patients (70.8%) were included in the pAMPK-positive group (score >5). The Spearman's coefficient for the correlation between pAMPK and pACC scores in primary tumour samples was 0.514 (P=0.0002). Low pAMPK levels were associated with worse OS (P-value 0.0002) but not with PFS, whereas low pACC levels were associated both with worse OS and PFS (P-value 0.0007 and 0.01, respectively). CONCLUSIONS: Our findings suggest that high tissue AMPK activation is a prognostic biomarker in this cohort of metastatic colorectal cancer patients.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/enzimología , Adulto , Anciano , Inhibidores de la Angiogénesis/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Bevacizumab , Biomarcadores de Tumor/metabolismo , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Activación Enzimática , Femenino , Fluorouracilo/administración & dosificación , Humanos , Inmunohistoquímica , Irinotecán , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
The liver kinase B1 (LKB1) gene is a tumor suppressor associated with the hereditary Peutz-Jeghers syndrome and frequently mutated in non-small cell lung cancer and in cervical cancer. Previous studies showed that the LKB1/AMPK axis is involved in regulation of cell death and survival under metabolic stress. By using isogenic pairs of cancer cell lines, we report here that the genetic loss of LKB1 was associated with increased intracellular levels of total choline containing metabolites and, under oxidative stress, it impaired maintenance of glutathione (GSH) levels. This resulted in markedly increased intracellular reactive oxygen species (ROS) levels and sensitivity to ROS-induced cell death. These effects were rescued by re-expression of LKB1 or pre-treatment with the anti-oxidant and GSH replenisher N-acetyl cysteine. This role of LKB1 in response to ROS-inducing agents was largely AMPK-dependent. Finally, we observed that LKB1 defective cells are highly sensitive to cisplatin and γ-irradiation in vitro, suggesting that LKB1 mutated tumors could be targeted by oxidative stress-inducing therapies.
Asunto(s)
Cisplatino/farmacología , Rayos gamma , Glutatión/metabolismo , Peróxido de Hidrógeno/farmacología , Estrés Oxidativo/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/metabolismo , Quinasas de la Proteína-Quinasa Activada por el AMP , Antineoplásicos/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Humanos , Espectroscopía de Resonancia Magnética , Proteínas Serina-Treonina Quinasas/genéticaRESUMEN
CONTEXT AND OBJECTIVE: Subcutaneous adipose tissue (SAT) lipoatrophy (LA) is a rare complication of insulin therapy. We aimed to analyze the ultrastructural and molecular aspects of LA lesions. SETTING AND PATIENTS: Macroscopic and microscopic morphology of SAT beneath the LA areas from patients with type 1 diabetes treated with Lispro insulin by continuous sc insulin infusion was studied using magnetic resonance imaging, immunohistochemistry, electron microscopy, and quantitative PCR for adipose tissue-specific genes. RESULTS: SAT was present in LA lesions characterized by: 1) smaller, unilocular perilipin-positive adipocytes, with lipofuscin granules; 2) some "slimmed cells" losing lipid droplets as those we observed during starvation; and 3) numerous perivascular preadipocytes. We did not identify inflammatory cells. SAT in LA areas displayed a strong leptin down-regulation and an increase of AEBP1, a preadipocyte marker. CONCLUSIONS: Our results clearly indicate that the remarkable reduction in fat cell lipid droplets and adipocyte size justifies the decrease of SAT without a reduction in adipocyte number because of necrosis or apoptosis. Thus, immune cells and any other toxic damaging fat cells were not involved in the generation of LA. We speculate that adipocytes chronically exposed to high local insulin concentrations could become severely insulin resistant, dramatically increasing lipolysis and giving rise to "slimmed cells." Clinical LA regression could be explained by the active recruitment of preadipocytes, even if they were unable to differentiate and regenerate adipose tissue unless the insulin injection was removed.
Asunto(s)
Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/ultraestructura , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Infusiones Subcutáneas/efectos adversos , Insulina/efectos adversos , Tejido Adiposo/metabolismo , Tejido Adiposo/patología , Adulto , Análisis de Varianza , Atrofia , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Masculino , Microscopía Electrónica de Transmisión , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Es presentada una paciente con el sindrome de hipoplasia femoral-facies rara (SHF-FR) Dentro del patron de malformaciones descripto para este sindrome, las caracteristicas faciales que presento esta nina corresponderian a los casos intermedios, siendo una contribucion mas a favor de la hipotesis de que el SHF-FR representa el final del espectro de un complejo malformativo de expresividad variable y no existiria como entidad sindromica especifica