Combined pitavastatin and capmatinib inhibits tumor growth though completed shutdown of MET signal
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ABSTRACT:
PROVIDER: PRJNA607759 | ENA |
REPOSITORIES: ENA
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Project description:To reveal the function of pitavastatin in cancer, we performed several experiments. In the present study, we show that pitavastatin inhibits the tumor growth through the inactivation of ERK and AKT signals by MET immaturation, and combination of pitavastatin and capmatinib, a MET inhibitor, might be useful cancer therapy in OSCC and ESCC. It could be reduced the dose of pitavastatin by using this combination therapy, resulting in decreasing the risk of adverse events such as myopathy. Taken together, the mevalonate pathway regulates the processes of MET maturation and promotes the cell growth in cancer. Moreover, the expression of GGPS1, an enzyme that synthesizes geranylgeranyl pyrophosphate (GGPP) from farnesyl pyrophosphate (FPP), associates with the sensitivity of pitavastatin, suggesting that GGPS1 could be a biomarker in cancer therapy with pitavastatin. Identification of the function of pitavastatin in oral and esophageal squamous cell carcinoma.
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Project description:In animals, the piRNA pathway preserves the integrity of gametic genomes, guarding them against the activity of mobile genetic elements. This innate immune mechanism relies on distinct genomic loci, termed piRNA clusters, to provide a molecular definition of transposons, enabling their discrimination from genes. piRNA clusters give rise to long, single-stranded precursors which are processed into primary piRNAs through an unknown mechanism. These can engage in an adaptive amplification loop, the ping-pong cycle, to optimize the content of small RNA populations via the generation of secondary piRNAs. Many proteins have been ascribed functions in either primary biogenesis or the ping- pong cycle, though for the most part the molecular functions of proteins implicated in these pathways remain obscure. Here, we link shutdown, a gene previously shown to be required for fertility in Drosophila, to the piRNA pathway. Analysis of knockdown phenotypes in both the germ line and somatic compartments of the ovary demonstrate important roles for shutdown in both primary biogenesis and the ping-pong cycle. shutdown is a member of the FKBP family of immunophilins, with domains implicated in peptidyl-prolyl cis-trans isomerase activity and in the binding of HSP90-family chaperones. Though the relevance of these domains to piRNA biogenesis is unknown, evolutionary comparisons raise questions about the integrity of these functions in the shutdown protein. Examination of small RNA levels from nos-GAL4 or tj-GAL4 driven UAS-dsRNA knockdowns of white, shu and piwi in ovaries of Drosophila melanogaster by deep sequencing (using Illumina GAII).
2012-06-30 | E-GEOD-38089 | biostudies-arrayexpress
Project description:In animals, the piRNA pathway preserves the integrity of gametic genomes, guarding them against the activity of mobile genetic elements. This innate immune mechanism relies on distinct genomic loci, termed piRNA clusters, to provide a molecular definition of transposons, enabling their discrimination from genes. piRNA clusters give rise to long, single-stranded precursors which are processed into primary piRNAs through an unknown mechanism. These can engage in an adaptive amplification loop, the ping-pong cycle, to optimize the content of small RNA populations via the generation of secondary piRNAs. Many proteins have been ascribed functions in either primary biogenesis or the ping-pong cycle, though for the most part the molecular functions of proteins implicated in these pathways remain obscure. Here, we link shutdown, a gene previously shown to be required for fertility in Drosophila, to the piRNA pathway. Analysis of knockdown phenotypes in both the germline and somatic compartments of the ovary demonstrate important roles for shutdown in both primary biogenesis and the ping-pong cycle. shutdown is a member of the FKBP family of immunophilins. Shu contains domains implicated in peptidyl-prolyl cis-trans isomerase activity and in the binding of HSP90-family chaperones, though the relevance of these domains to piRNA biogenesis is unknown. Analysis of mRNA expression in Drosophila OSS cells transfected with GFP dsRNA. One sample and replicate, used to establish the OSS baseline transcriptome in the presence of exogenous RNAi activity.
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Project description:In animals, the piRNA pathway preserves the integrity of gametic genomes, guarding them against the activity of mobile genetic elements. This innate immune mechanism relies on distinct genomic loci, termed piRNA clusters, to provide a molecular definition of transposons, enabling their discrimination from genes. piRNA clusters give rise to long, single-stranded precursors which are processed into primary piRNAs through an unknown mechanism. These can engage in an adaptive amplification loop, the ping-pong cycle, to optimize the content of small RNA populations via the generation of secondary piRNAs. Many proteins have been ascribed functions in either primary biogenesis or the ping- pong cycle, though for the most part the molecular functions of proteins implicated in these pathways remain obscure. Here, we link shutdown, a gene previously shown to be required for fertility in Drosophila, to the piRNA pathway. Analysis of knockdown phenotypes in both the germ line and somatic compartments of the ovary demonstrate important roles for shutdown in both primary biogenesis and the ping-pong cycle. shutdown is a member of the FKBP family of immunophilins, with domains implicated in peptidyl-prolyl cis-trans isomerase activity and in the binding of HSP90-family chaperones. Though the relevance of these domains to piRNA biogenesis is unknown, evolutionary comparisons raise questions about the integrity of these functions in the shutdown protein.
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Project description:In animals, the piRNA pathway preserves the integrity of gametic genomes, guarding them against the activity of mobile genetic elements. This innate immune mechanism relies on distinct genomic loci, termed piRNA clusters, to provide a molecular definition of transposons, enabling their discrimination from genes. piRNA clusters give rise to long, single-stranded precursors which are processed into primary piRNAs through an unknown mechanism. These can engage in an adaptive amplification loop, the ping-pong cycle, to optimize the content of small RNA populations via the generation of secondary piRNAs. Many proteins have been ascribed functions in either primary biogenesis or the ping-pong cycle, though for the most part the molecular functions of proteins implicated in these pathways remain obscure. Here, we link shutdown, a gene previously shown to be required for fertility in Drosophila, to the piRNA pathway. Analysis of knockdown phenotypes in both the germline and somatic compartments of the ovary demonstrate important roles for shutdown in both primary biogenesis and the ping-pong cycle. shutdown is a member of the FKBP family of immunophilins. Shu contains domains implicated in peptidyl-prolyl cis-trans isomerase activity and in the binding of HSP90-family chaperones, though the relevance of these domains to piRNA biogenesis is unknown.
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Project description:Pediatric high-grade glioma (pHGG) is the most frequent malignant brain tumor in children and can be subclassified into multiple entities. Fusion genes activating the MET receptor tyrosine kinase often occur in infant-type hemispheric glioma (iHG) but also in other pHGGs, and are associated with devastating morbidity and mortality. To identify new treatment options, we established and characterized two novel orthotopic mouse models harboring distinct MET fusions. These included an immunocompetent, murine allograft model and patient-derived orthotopic xenografts (PDOX) from a MET-fusion iHG patient who failed conventional therapy and targeted therapy with cabozantinib. With these models, we analyzed the efficacy and pharmacokinetic properties of three MET inhibitors, capmatinib, crizotinib and cabozantinib, alone or combined with radiotherapy (RT). The PDOX models recapitulated the poor efficacy of cabozantinib experienced by the patient. In contrast, capmatinib showed superior brain pharmacokinetic properties and greater in vitro and in vivo efficacy than cabozantinib or crizotinib. Strikingly, capmatinib treated mice displayed long-term progression-free survival (PFS) when combined with radiotherapy in two complementary mouse models. Molecular analysis of the treated tumors revealed impaired DNA repair after MET inhibition as a plausible mechanism of radiosensitization. We comprehensively investigated the combination of MET inhibition and radiotherapy as a novel treatment option for MET-driven pHGG. Our seminal preclinical data package includes pharmacokinetic characterization, recapitulation of clinical outcomes, coinciding results from multiple complementing in vivo studies and a plausible molecular mechanism. We thereby demonstrate the groundbreaking efficacy of capmatinib and radiation, as a highly promising concept for future clinical trials.
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