Cryptotanshinone suppresses key onco-proliferative and drug-resistant pathways of chronic myeloid leukemia by targetingSTAT5 and STAT3 phosphorylation

• 来源期刊: 中国科学（生命科学）
• 年，卷（期）: 2018,（9）
• 页码范围: 999-1009
• 页数: 11页
• 语种: 中文

摘要

C-Myc and signal transducer and activator of transcription (STAT) family proteins have been proposed to be important downstream genes of BCR-ABL,which characterizes most cases of chronic myeloid leukemia (CML).Here,we report a c-Myc pathway-targeted screening of seven natural anticancer compounds,in which we identified cryptotanshinone as a highly promising agent for CML therapy.Cryptotanshinone depletes c-Myc in CML by repressing the phosphorylation of STAT5.Decreased viability ofK562 cells correlated with p-STAT5 suppression.Unexpectedly,imatinib activates rather than inhibits the phosphorylation of STAT3 in K562 cells.We demonstrated that cryptotanshinone,as a dual inhibitor of p-STAT5 and p-STAT3,can effectively block IL-6-mediated STAT3 activation and reverse BCR-ABL kinase-independent drug resistance.Moreover,we showed that the epigenetic rebalance between decreased BCR-ABL/STAT5/c-Myc and enhanced STAT3/multi-drug resistance (MDR) pathways is characteristic of the cancer stem cell-like property of K562/ADR.Simultaneously suppressing these two pathways using cryptotanshinone proves to be critical for the malignant network redress and MDR reversal of K562/ADR.These studies reveal the dual functions of cryptotanshinone that suppress key oncogenic proliferation and drug-resistant pathways in CML cells by targeting p-STAT5 and p-STAT3,providing a new strategy for CML therapy that takes advantage of natural products.