Cryptotanshinone suppresses key onco-proliferative and drug-resistant pathways of chronic myeloid leukemia by targeting STAT5 and STAT3 phosphorylation
Cryptotanshinone suppresses key onco-proliferative and drug-resistant pathways of chronic myeloid leukemia by targeting STAT5 and STAT3 phosphorylation
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隐丹参酮通过靶向 STAT5 和 STAT3 磷酸化抑制慢性粒细胞白血病的关键肿瘤增殖和耐药途径
DOI：
10.1007/s11427-018-9324-y
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发表时间：
2018-09-01
影响因子：
9.1
通讯作者：
Qu, Lianghu
中科院分区：
文献类型：
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作者：
Dong, Bowen;Liang, Zirui;Qu, Lianghu
C-Myc和信号转导和转录激活因子（STAT）家族蛋白被认为是BCR-ABL的重要下游基因，而BCR-ABL是大多数慢性粒细胞白血病（CML）的特征。在这里，我们报告了一个c-Myc通路为靶向筛选的7种天然抗癌化合物，其中我们确定隐丹参酮作为一个非常有前途的药物治疗慢性粒细胞白血病。隐丹参酮通过抑制STAT 5的磷酸化来耗尽CML中的c-Myc。K562细胞活力下降与p-STAT 5抑制相关。出乎意料的是，伊马替尼在K562细胞中激活而不是抑制STAT 3的磷酸化。我们证明隐丹参酮作为p-STAT 5和p-STAT 3的双重抑制剂，可以有效地阻断IL-6介导的STAT 3激活，逆转BCR-ABL激酶非依赖性耐药。此外，我们发现，减少BCR-ABL/STAT 5/c-Myc和增强STAT 3/多药耐药（MDR）途径之间的表观遗传再平衡是K562/ADR的肿瘤干细胞样特性的特征。隐丹参酮同时抑制这两条通路对K562/ADR的恶性网络纠正和MDR逆转至关重要。这些研究揭示了隐丹参酮通过靶向p-STAT 5和p-STAT 3抑制CML细胞中关键致癌增殖和耐药途径的双重功能，为利用天然产物治疗CML提供了新的策略。
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.