{"id":1244,"date":"2019-07-21T21:33:07","date_gmt":"2019-07-21T13:33:07","guid":{"rendered":"http:\/\/www.bioactivescreeninglibrary.com\/?p=1244"},"modified":"2022-01-07T10:54:01","modified_gmt":"2022-01-07T02:54:01","slug":"cytostatic-response-rapamycin-induce-apoptosis-combined-agents","status":"publish","type":"post","link":"http:\/\/www.bioactivescreeninglibrary.com\/index.php\/2019\/07\/21\/cytostatic-response-rapamycin-induce-apoptosis-combined-agents\/","title":{"rendered":"Cytostatic response than rapamycin and can induce apoptosis especially when combined with other agents"},"content":{"rendered":"

The greater biological effects of asTORi relative to rapamycin have been linked to differential effects on the 4EBP-eIF4E axis. Supporting this correlation, Y-27632 dihydrochloride<\/a> recent studies have shown that reducing the ratio of 4EBP to eIF4E expression in experimental cell lines can increase sensitivity to asTORi. Diffuse large B-cell lymphoma is a common hematological malignancy for which new therapeutic strategies are needed. Targeting mTOR with asTORi represents a potential new approach. Here we report the discovery of a DLBCL line, VAL, which is intrinsically resistant to asTORi and lacks detectable expression of 4EBP1 mRNA or protein. 4EBP2 is expressed in VAL cells but does not block formation of the capbinding complex following mTOR inhibition. In accord, asTORi fail to inhibit expression of a cap-dependent ICG-001<\/a> reporter plasmid and have minimal effects on protein synthesis in VAL cells. Knockdown of eIF4E or expression of 4EBP1 sensitizes VAL cells to asTORi. Low expression of 4EBP1 in a primary human DLBCL specimen was reported in a microarray study, and eIF4E overexpression is quite common. Our data suggest that low 4EBP1 expression and\/or high eIF4E expression might be negative predictive markers for asTORi efficacy in lymphoma. In this study we have identified a human DLBCL line whose resistance to asTORi can be attributed in part to a low ratio of 4EBP\/eIF4E expression. VAL cells lack protein expression of 4EBP1, a key inhibitor of eIF4F formation. Although the cells express 4EBP2, treatment with asTORi fails to displace eIF4G from eIF4E and causes minimal inhibition of cap-dependent translation and protein synthesis. Knocking down eIF4E or adding back 4EBP1 can help circumvent the resistance to asTORi, sensitizing cap dependent translation and potentiating cell death. Our results agree with recent findings that the 4EBP\/eIF4E ratio is a crucial determinant of asTORi sensitivity in cancer cells, and extend this model to a naturally occurring DLBCL line deficient in 4EBP1. Our data suggest that reduced 4EBP expression might be a biomarker of resistance to asTORi and to dual PI3K\/mTOR inhibitors in DLBCL and other blood cancers. Of note, the OCILY3, RCK-8 and SU-DHL5 cell lines had reduced amounts of 4EBP1 compared to other cell lines and were mostly resistant to asTORi-induced death. However, asTORi still reduced cap dependent translation in these cell lines as judged by reporter assays. We focused our additional studies on VAL cells in which 4EBP1 mRNA and protein were absent and cap dependent translation was resistant to asTORi. Although we could readily detect 4EBP2 protein in cell lysates and cap-binding assays, the presence of this isoform is not sufficient to confer asTORi sensitivity in VAL cells lacking 4EBP1. We cloned and sequenced the cDNAs for eIF4F components expressed in VAL cells and did not identify any mutations that might explain the preservation of eIF4G binding upon asTORi-induced recruitment of 4EBP2. We did not measure expression of the third isoform, 4EBP3, but if it is present in VAL cells it also cannot substitute for 4EBP1. If eIF4E expression is in excess of eIF4G and 4EBP2 in VAL cells, this might explain why asTORi-triggered 4EBP2 recruitment does not affect eIF4G binding. Consistent with this model, eIF4E knockdown rendered VAL cells sensitive to asTORi effects on capdependent translation and cell death. In VAL cells with eIF4E knockdown, MLN0128 reduced MCL-1 expression and this might contribute to the increased apoptosis. In addition to conferring mTOR inhibitor resistance, a reduced 4EBP:eIF4E ratio might help to drive the tumor phenotype by facilitating translation of oncogenic mRNAs. eIF4E overexpression has been noted in many cancer types, and eIF4E overexpression in a mouse model cooperated with Myc to cause B cell transformation.<\/p>\n","protected":false},"excerpt":{"rendered":"

The greater biological effects of asTORi relative to rapamycin have been linked to differential effects on the 4EBP-eIF4E axis. Supporting this correlation, Y-27632 dihydrochloride recent studies have shown that reducing the ratio of 4EBP to eIF4E expression in experimental cell lines can increase sensitivity to asTORi. Diffuse large B-cell lymphoma is a common hematological malignancy … Continue reading “Cytostatic response than rapamycin and can induce apoptosis especially when combined with other agents”<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":[],"categories":[1],"tags":[],"_links":{"self":[{"href":"http:\/\/www.bioactivescreeninglibrary.com\/index.php\/wp-json\/wp\/v2\/posts\/1244"}],"collection":[{"href":"http:\/\/www.bioactivescreeninglibrary.com\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"http:\/\/www.bioactivescreeninglibrary.com\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"http:\/\/www.bioactivescreeninglibrary.com\/index.php\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"http:\/\/www.bioactivescreeninglibrary.com\/index.php\/wp-json\/wp\/v2\/comments?post=1244"}],"version-history":[{"count":1,"href":"http:\/\/www.bioactivescreeninglibrary.com\/index.php\/wp-json\/wp\/v2\/posts\/1244\/revisions"}],"predecessor-version":[{"id":1245,"href":"http:\/\/www.bioactivescreeninglibrary.com\/index.php\/wp-json\/wp\/v2\/posts\/1244\/revisions\/1245"}],"wp:attachment":[{"href":"http:\/\/www.bioactivescreeninglibrary.com\/index.php\/wp-json\/wp\/v2\/media?parent=1244"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"http:\/\/www.bioactivescreeninglibrary.com\/index.php\/wp-json\/wp\/v2\/categories?post=1244"},{"taxonomy":"post_tag","embeddable":true,"href":"http:\/\/www.bioactivescreeninglibrary.com\/index.php\/wp-json\/wp\/v2\/tags?post=1244"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}