AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA 163 Purpose of the study: Malignant pleural ... more AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA 163 Purpose of the study: Malignant pleural mesothelioma is a disease with a poor prognosis and a median survival time of only 1 year. Thus, it is very essential to find potential new therapies for mesothelioma and thereby identify new targets regulated by cap-dependent translation in this cancer. 4EGI-1 inhibits the interaction between translation initiation factors eIF4E and eIF4G and thus inhibits cap-dependent translation in other cancers. Here, we study the effect of 4EGI-1 on cap-dependent translation in mesothelioma. Methods: Human mesothelioma cell lines H2596 and H2461 and the non-transformed human mesothelial cell line LP9 were used for these studies. Proliferation studies using the Cell Counting Kit-8 were performed. Cap-binding assay using the 7-methyl-GTP-Sepharose resin was done to study the inhibition of the formation of the cap-dependent translation initiation complex. Western blot analysis was used to evaluate the...
Deregulation of cap-dependent translation has been implicated in the malignant transformation of ... more Deregulation of cap-dependent translation has been implicated in the malignant transformation of numerous human tissues. 4EGI-1, a novel small-molecule inhibitor of cap-dependent translation, disrupts formation of the eukaryotic initiation factor 4F (eIF4F) complex. The effects of 4EGI-1-mediated inhibition of translation initiation in malignant pleural mesothelioma (MPM) were examined. 4EGI-1 preferentially inhibited cell viability and induced apoptosis in MPM cells compared to normal mesothelial (LP9) cells. This effect was associated with hypophosphorylation of 4E-binding protein 1 (4E-BP1) and decreased protein levels of the cancer-related genes, c-myc and osteopontin. 4EGI-1 showed enhanced cytotoxicity in combination with pemetrexed or gemcitabine. Translatome-wide polysome microarray analysis revealed a large cohort of genes that were translationally regulated upon treatment with 4EGI-1. The 4EGI-1-regulated translatome was negatively correlated to a previously published tran...
AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA 163 Purpose of the study: Malignant pleural ... more AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA 163 Purpose of the study: Malignant pleural mesothelioma is a disease with a poor prognosis and a median survival time of only 1 year. Thus, it is very essential to find potential new therapies for mesothelioma and thereby identify new targets regulated by cap-dependent translation in this cancer. 4EGI-1 inhibits the interaction between translation initiation factors eIF4E and eIF4G and thus inhibits cap-dependent translation in other cancers. Here, we study the effect of 4EGI-1 on cap-dependent translation in mesothelioma. Methods: Human mesothelioma cell lines H2596 and H2461 and the non-transformed human mesothelial cell line LP9 were used for these studies. Proliferation studies using the Cell Counting Kit-8 were performed. Cap-binding assay using the 7-methyl-GTP-Sepharose resin was done to study the inhibition of the formation of the cap-dependent translation initiation complex. Western blot analysis was used to evaluate the...
Deregulation of cap-dependent translation has been implicated in the malignant transformation of ... more Deregulation of cap-dependent translation has been implicated in the malignant transformation of numerous human tissues. 4EGI-1, a novel small-molecule inhibitor of cap-dependent translation, disrupts formation of the eukaryotic initiation factor 4F (eIF4F) complex. The effects of 4EGI-1-mediated inhibition of translation initiation in malignant pleural mesothelioma (MPM) were examined. 4EGI-1 preferentially inhibited cell viability and induced apoptosis in MPM cells compared to normal mesothelial (LP9) cells. This effect was associated with hypophosphorylation of 4E-binding protein 1 (4E-BP1) and decreased protein levels of the cancer-related genes, c-myc and osteopontin. 4EGI-1 showed enhanced cytotoxicity in combination with pemetrexed or gemcitabine. Translatome-wide polysome microarray analysis revealed a large cohort of genes that were translationally regulated upon treatment with 4EGI-1. The 4EGI-1-regulated translatome was negatively correlated to a previously published tran...
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