Inhibition of KLF4 by Statins Reverses Adriamycin-Induced Metastasis and Cancer Stemness in Osteosarcoma Cells.
Inhibition of KLF4 by Statins Reverses Adriamycin-Induced Metastasis and Cancer Stemness in Osteosarcoma Cells.
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DOI：
10.1016/j.stemcr.2017.04.025
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发表时间：
2017-06-06
影响因子：
5.9
通讯作者：
He Q
中科院分区：
文献类型：
--
作者：
Li Y;Xian M;Yang B;Ying M;He Q
以阿霉素为基础的联合化疗是骨肉瘤的标准一线治疗方法，但大多数病例会发生肿瘤复发和转移。最近的证据表明，微环境应激（如化疗）可导致癌症干细胞（CSC）富集，从而导致癌症转移、复发和耐药性。然而，这种现象背后的确切机制以及如何靶向CSC仍然是悬而未决的问题。在此，我们报告阿霉素治疗诱导干细胞样表型，并通过上调KLF 4促进骨肉瘤细胞的转移潜力。KLF 4敲低阻断阿霉素诱导的干性表型和转移能力我们进一步筛选他汀类药物通过下调KLF 4显著逆转阿霉素诱导的CSC特性和转移。最引人注目的是，辛伐他汀严重损害阿霉素增强的KHOS/NP细胞在体内的肿瘤发生。这些数据表明，基于阿霉素的化疗药物可能通过激活KLF 4信号传导来刺激CSC，并且在骨肉瘤治疗药物的开发中应考虑使用他汀类药物选择性抑制KLF 4。阿霉素处理诱导骨肉瘤细胞中的干性表型KLF 4是ADR诱导的骨肉瘤癌症干性的关键转录调节因子辛伐他汀通过下调KLF 4逆转ADR诱导的CSC特性辛伐他汀消除体内KHOS/NP细胞的ADR增强的肿瘤发生在这篇文章中，Ying，He，和同事们的研究表明，阿霉素-的化疗剂可以通过激活KLF 4信号传导和用他汀类药物，降胆固醇剂，显著逆转阿霉素诱导的CSC特性和骨肉瘤转移。他们的研究结果表明，在骨肉瘤治疗药物的开发中可以考虑用他汀类药物靶向KLF 4。
Adriamycin-based combination chemotherapy is the standard first-line treatment for osteosarcoma, but tumor recurrence and metastasis occurs in most cases. Recent evidence suggests that microenvironmental stress such as chemotherapy can lead to the enrichment of cancer stem cells (CSCs), which result in cancer metastasis, recurrence, and drug resistance. However, the exact mechanisms underlying this phenomenon and how to target CSCs are still open questions. Herein, we report that Adriamycin treatment induces a stem-like phenotype and promotes metastatic potential in osteosarcoma cells through upregulating KLF4. KLF4 knockdown blocks Adriamycin-induced stemness phenotype and metastasis capacity. We further screen that statins remarkably reverse Adriamycin-induced CSC properties and metastasis by downregulating KLF4. Most strikingly, simvastatin severely impaired Adriamycin-enhanced tumorigenesis of KHOS/NP cells in vivo. These data suggest that Adriamycin-based chemotherapeutics may simulate CSCs through activation of KLF4 signaling and that selective inhibition of KLF4 with statins should be considered in the development of osteosarcoma therapeutics. Adriamycin treatment induces a stemness phenotype in osteosarcoma cells KLF4 is a key transcriptional regulator of ADR-induced osteosarcoma cancer stemness Simvastatin reverses ADR-induced CSC properties by downregulating KLF4 Simvastatin abolishes ADR-enhanced tumorigenesis of KHOS/NP cells in vivo In this article, Ying, He, and colleagues show that Adriamycin-based chemotherapeutics may simulate CSCs through activation of KLF4 signaling and that selective inhibition of KLF4 with statins, the cholesterol-lowering agents, remarkably reverse the Adriamycin-induced CSC properties and metastasis in osteosarcoma. Their findings suggest that targeting of KLF4 with statins may be considered in the development of osteosarcoma therapeutics.