RESUMEN
Glioma is the most common primary intracranial tumor, in which glioblastoma (GBM) is the most malignant and lethal. However, the current chemotherapy drugs are still unsatisfactory for GBM therapy. As the natural products mainly extracted from Eucalyptus species, phloroglucinol-terpene adducts have the potential to be anti-cancer lead compounds that attracted increasing attention. In order to discover the new lead compounds with the anti-GBM ability, we isolated Eucalyptal A with a phloroglucinol-terpene skeleton from the fruit of E. globulus and investigated its anti-GBM activity in vitro and in vivo. Functionally, we verified that Eucalyptal A could inhibit the proliferation, growth and invasiveness of GBM cells in vitro. Moreover, Eucalyptal A had the same anti-GBM activity in tumor-bearing mice as in vitro and prolonged the overall survival time by maintaining mice body weight. Further mechanism research revealed that Eucalyptal A downregulated SRSF1 expression and rectified SRSF1-guided abnormal alternative splicing of MYO1B mRNA, which led to anti-GBM activity through the PDK1/AKT/c-Myc and PAK/Cofilin axes. Taken together, we identified Eucalyptal A as an important anti-GBM lead compound, which represents a novel direction for glioma therapy.
Asunto(s)
Neoplasias Encefálicas/metabolismo , Carcinogénesis/efectos de los fármacos , Eucaliptol/uso terapéutico , Glioma/metabolismo , Miosina Tipo I/metabolismo , Empalme de Proteína/efectos de los fármacos , Factores de Empalme Serina-Arginina/biosíntesis , Animales , Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/uso terapéutico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/prevención & control , Carcinogénesis/metabolismo , Carcinogénesis/patología , Línea Celular Tumoral , Medicamentos Herbarios Chinos/aislamiento & purificación , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Eucaliptol/aislamiento & purificación , Eucaliptol/farmacología , Regulación Neoplásica de la Expresión Génica , Glioma/genética , Glioma/prevención & control , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Miosina Tipo I/genética , Empalme de Proteína/fisiología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factores de Empalme Serina-Arginina/antagonistas & inhibidores , Factores de Empalme Serina-Arginina/genética , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
Myosins are actin-based molecular motors that are found in almost all eukaryotes. Phylogenetic analysis allows the discrimination of 37 different types of myosins, most with unknown functions. Recent work in Drosophila has revealed a crucial role for type ID unconventional myosin in left-right asymmetry. Mutations in Myosin ID completely reverse the left-right axis (situs inversus), a phenotype that is dependent on an intact actin cytoskeleton. How this myosin might orient the left-right axis has began to be elucidated by showing that it interacts directly with beta-catenin, suggesting that myosin ID interacts with the adherens junction to control the direction of organ looping. This is the first demonstration of a role of a myosin in body patterning.
Asunto(s)
Citoesqueleto/fisiología , Miosina Tipo I/fisiología , Uniones Adherentes/fisiología , Animales , Tipificación del Cuerpo/fisiología , Calcio/fisiología , Proteínas de Drosophila/fisiología , Drosophila melanogaster/embriología , Drosophila melanogaster/fisiología , Miosina Tipo I/genética , Miosinas/fisiología , Transporte de ProteínasRESUMEN
We analysed a complex translocation involving chromosomes 7, 11, 19 and 22 in infant acute monocytic leukemia, and identified that the MLL gene on 11q23 was fused to the unconventional myosin type 1F, MYO1F, gene on 19p13.2-13.3. MYO1F consists of at least 28 exons and was predicted to encode a 1098-amino-acid with an N-terminal head domain containing both ATP-binding and actin-binding sequences, a neck domain with a single IQ motif, and a tail with TH1, TH2 and SH3 domains. Northern blot analysis of RNAs prepared from multiple tissues showed that the expression of approximately 4-kb transcripts appeared constant in most tissues examined. However, MYO1F was expressed in only three of 22 leukemic cell lines. The MLL-MYO1F fusion protein contains almost the entire MYO1F, however, C-terminal MYO1F has neither the transactivation domain nor the dimerization domain found in various MLL fusion partners. Further analysis of this novel type of MLL fusion protein would provide new insights into leukemogenesis. MYO1F is the fourth partner gene of MLL on 19p13. At the cytogenetic level, it may be difficult to distinguish MLL-ENL, MLL-ELL, MLL-EEN and MLL-MYO1F fusions created by t(11;19)(q23;p13), and it is likely that cases of t(11;19) lacking a known fusion gene may result in this gene fusion.