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

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Abstract

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.

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Acknowledgements

We thank Qiaojuan Huang and Xiaohong Chen for their technical assistances. This work was supported by the National Natural Science Foundation of China (31471223, 31230042, 31771459, 31770879), the Project of Science and Technology of Guangzhou (201504010022) and the National Key R&D Program of China (2017YFA0504400) from the Ministry of Science and Technology of China.

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  1. Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou, 510275, China

    Bowen Dong, Zirui Liang, Zhirong Chen, Bin Li, Lingling Zheng, Jianhua Yang, Hui Zhou & Lianghu Qu

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  1. Bowen Dong
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  2. Zirui Liang
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  8. Lianghu Qu
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Correspondence to Lianghu Qu.

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Dong, B., Liang, Z., Chen, Z. et al. Cryptotanshinone suppresses key onco-proliferative and drug-resistant pathways of chronic myeloid leukemia by targeting STAT5 and STAT3 phosphorylation. Sci. China Life Sci. 61, 999–1009 (2018). https://doi.org/10.1007/s11427-018-9324-y

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