Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Room 427, Hangzhou 310058, China.
Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Room 427, Hangzhou 310058, China.
Stem Cell Reports. 2017 Jun 6;8(6):1617-1629. doi: 10.1016/j.stemcr.2017.04.025. Epub 2017 May 25.
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.
阿霉素为基础的联合化疗是骨肉瘤的标准一线治疗方法，但大多数情况下会发生肿瘤复发和转移。最近的证据表明，微环境压力（如化疗）会导致癌症干细胞（CSC）的富集，从而导致癌症转移、复发和耐药。然而，这种现象的确切机制以及如何针对 CSC 仍然是悬而未决的问题。在此，我们报告阿霉素治疗通过上调 KLF4 诱导骨肉瘤细胞产生类干细胞表型并促进其转移潜能。KLF4 敲低可阻断阿霉素诱导的干性表型和转移能力。我们进一步筛选发现，他汀类药物通过下调 KLF4 显著逆转阿霉素诱导的 CSC 特性和转移。最引人注目的是，辛伐他汀在体内严重损害了阿霉素增强的 KHOS/NP 细胞的致瘤性。这些数据表明，阿霉素类化疗药物可能通过激活 KLF4 信号模拟 CSC，并且用他汀类药物选择性抑制 KLF4 应该在骨肉瘤治疗的开发中得到考虑。
