Wang Zhanxiang, Pelus Louis M
Department of Microbiology & Immunology, and the Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN 46202.
Cancer Ther. 2008;6(B):603-610.
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.
Bcr-abl激酶抑制剂STI571在大多数慢性粒细胞白血病（CML）患者中产生临床反应；然而，耐药性的产生限制了其效用。克服STI571耐药性的一种策略是降低Bcr-abl的水平/活性。我们报道，抗凋亡蛋白Survivin的破坏通过半胱天冬酶依赖性的Bcr-abl降解促进了STI571诱导的Bcr-abl(+) K562细胞凋亡。为了研究Survivin破坏在耐药CML细胞中的效用，我们通过用STI571长期培养产生了STI571耐药的K562细胞。与亲代细胞不同，在亲代细胞中Survivin破坏增强了STI571诱导的凋亡，而在STI571耐药细胞中Survivin破坏未能促进STI571诱导的凋亡；相反，它保护细胞免受STI571和其他凋亡诱导化合物的影响。尽管亲代和STI571耐药的K562细胞中Survivin水平相似，但STI571耐药细胞中Survivin的破坏增加了端粒酶活性，这可能是由于Bcr-abl/c-abl降解所致。我们的结果表明，Bcr-abl(+) K562细胞中STI571耐药性的出现是由于诱导了其他规避STI571反应性的途径。
