RESUMEN
The neurofibromatosis type 2 (NF2) gene encodes merlin, a tumor suppressor protein frequently inactivated in schwannoma, meningioma, and malignant mesothelioma (MM). The sequence of merlin is similar to that of ezrin/radixin/moesin (ERM) proteins which crosslink actin with the plasma membrane, suggesting that merlin plays a role in transducing extracellular signals to the actin cytoskeleton. Merlin adopts a distinct closed conformation defined by specific intramolecular interactions and regulates diverse cellular events such as transcription, translation, ubiquitination, and miRNA biosynthesis, many of which are mediated through Hippo and mTOR signaling, which are known to be closely involved in cancer development. MM is a very aggressive tumor associated with asbestos exposure, and genetic alterations in NF2 that abrogate merlin's functional activity are found in about 40% of MMs, indicating the importance of NF2 inactivation in MM development and progression. In this review, we summarize the current knowledge of molecular events triggered by NF2/merlin inactivation, which lead to the development of mesothelioma and other cancers, and discuss potential therapeutic targets in merlin-deficient mesotheliomas.
Asunto(s)
Variación Genética , Neoplasias Pulmonares/genética , Mesotelioma/genética , Neurofibromina 2/genética , Actinas/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Vía de Señalización Hippo , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Mesotelioma/tratamiento farmacológico , Mesotelioma/metabolismo , Mesotelioma Maligno , Neurofibromina 2/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Malignant mesothelioma is an asbestos-related fatal disease with no effective cure. Recently, high dose of ascorbate in cancer treatment has been reexamined. We studied whether high dose of ascorbic acid induced cell death of four human mesothelioma cell lines. High dose of ascorbic acid induced cell death of all mesothelioma cell lines in a dose-dependent manner. We further clarified the cell killing mechanism that ascorbic acid induced reactive oxygen species and impaired mitochondrial membrane potential. In vivo experiment, intravenous administration of ascorbic acid significantly decreased the growth rate of mesothelioma tumor inoculated in mice. These data suggest that ascorbic acid may have benefits for patients with mesothelioma.
Asunto(s)
Apoptosis , Ácido Ascórbico/administración & dosificación , Mesotelioma/tratamiento farmacológico , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Ratones SCID , Especies Reactivas de Oxígeno/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The screening for active compounds against malignant pleural mesothelioma (MPM) cells produced by Streptomyces sp. AK-AB27 resulted in the isolation of two compounds with a dodecahydrodibenzo[b,d]furan skeleton named JBIR-23 (1) and -24 (2). Their structures were established on the basis of extensive NMR and MS analyses. Compounds 1 and 2 exhibited cytotoxic effects against several MPM cell lines.