{"title":"Disruption of Survivin in K562 cells elevates telomerase activity and protects cells against apoptosis induced by the Bcr-abl kinase inhibitor STI571.","authors":"Zhanxiang Wang, Louis M Pelus","doi":"","DOIUrl":null,"url":null,"abstract":"<p><p>The Bcr-abl kinase inhibitor STI571 produces clinical responses in most patients with Chronic Myeloid Leukemia (CML); however, development of resistance limits utility. One strategy to overcome STI571 resistance is to decrease the level/activity of Bcr-abl. We reported that disruption of the anti-apoptotic protein Survivin promoted STI571-induced apoptosis in Bcr-abl(+) K562 cells, through caspase-dependent Bcr-abl degradation. To investigate the utility of Survivin disruption in drug-resistant CML cells, we generated STI571-resistant K562 cells by long-term culture with STI571. In contrast to parental cells, where Survivin disruption enhances STI571-induced apoptosis, Survivin disruption in STI571-resistant cells failed to promote STI571-induced apoptosis; rather it protected cells from STI571 and other apoptosis-inducing compounds. Even though Survivin levels were similar in parental and STI571-resistant K562 cells, Survivin disruption in STI571-resistant cells increased telomerase activity, likely due to Bcr-abl/c-abl degradation. Our results indicate that emergence of STI571 resistance in Bcr-abl(+) K562 cells results from induction of additional pathways that circumvent STI571-responsiveness.</p>","PeriodicalId":87393,"journal":{"name":"Cancer therapy","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2600525/pdf/nihms70570.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer therapy","FirstCategoryId":"1085","ListUrlMain":"","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
Abstract
The Bcr-abl kinase inhibitor STI571 produces clinical responses in most patients with Chronic Myeloid Leukemia (CML); however, development of resistance limits utility. One strategy to overcome STI571 resistance is to decrease the level/activity of Bcr-abl. We reported that disruption of the anti-apoptotic protein Survivin promoted STI571-induced apoptosis in Bcr-abl(+) K562 cells, through caspase-dependent Bcr-abl degradation. To investigate the utility of Survivin disruption in drug-resistant CML cells, we generated STI571-resistant K562 cells by long-term culture with STI571. In contrast to parental cells, where Survivin disruption enhances STI571-induced apoptosis, Survivin disruption in STI571-resistant cells failed to promote STI571-induced apoptosis; rather it protected cells from STI571 and other apoptosis-inducing compounds. Even though Survivin levels were similar in parental and STI571-resistant K562 cells, Survivin disruption in STI571-resistant cells increased telomerase activity, likely due to Bcr-abl/c-abl degradation. Our results indicate that emergence of STI571 resistance in Bcr-abl(+) K562 cells results from induction of additional pathways that circumvent STI571-responsiveness.