The chimeric Bcr-Abl oncoprotein with constitutive tyrosine kinase activity plays a pivotal role in the pathogenesis of chronic myeloid leukemia (CML), therefore being an ideal target for the drug development. Although tyrosine kinase inhibitors achieved great success in the treatment of CML, their effect could be abrogated by mutation in the kinase domain where they bind to. Therefore inducing Bcr-Abl degradation could be an alternative strategy to treat Bcr-Abl-driven leukemia. Celastrol is a quinone methide triterpene with various biological activities including anticancer activity. In the current study, we reported that celastrol induced time-dependent Bcr-Abl degradation and apoptosis in K-562 CML cells. We also found that short-time exposure to celastrol was sufficient to induce committed apoptotic signal; removal of celastrol could cause re-expression of Bcr-Abl, which however cannot rescue the cell from undergoing apoptosis. In addition, we found that celastrol-induced Bcr-Abl degradation and cell apoptosis were not suppressed by commonly used protease inhibitors or their mixture under the selected experimental conditions. Our study clearly demonstrated that celastrol inhibits Bcr-Abl expression/function by inducing its degradation, which at least contributes to our understanding of this natural product�s ability to induce tumor cell apoptosis. Our finding strongly supports the idea that celastrol could be developed into a novel anti-CML drug.
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