Cryptotanshinone suppresses key onco-proliferative and drugresistant pathways of chronic myeloid leukemia by targeting STAT5 and STAT3 phosphorylation  被引量:13

Cryptotanshinone suppresses key onco-proliferative and drugresistant pathways of chronic myeloid leukemia by targeting STAT5 and STAT3 phosphorylation

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作  者:Bowen Dong Zirui Liang Zhirong Chen Bin Li Lingling Zheng Jianhua Yang Hui Zhou Lianghu Qu 

机构地区:[1]Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory for Biocontrol, Sun Yat-sen University

出  处:《Science China(Life Sciences)》2018年第9期999-1009,共11页中国科学(生命科学英文版)

基  金:supported by the National Natural Science Foundation of China (31471223, 31230042, 31771459, 31770879);the Project of Science and Technology of Guangzhou (201504010022);the National Key R&D Program of China (2017YFA0504400) from the Ministry of Science and Technology of China

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 of K562 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.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 of K562 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.

关 键 词:p-STAT3/5 microRNA CML MDR 

分 类 号:R733.72[医药卫生—肿瘤]

 

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