Division of Medical Genetics and Genomics, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Institute of Genetics, Zhejiang University, Hangzhou, Zhejiang, China.
Ningbo No.4 Hospital, Ningbo, Zhejiang, China.
Cancer Lett. 2018 Jul 1;425:1-12. doi: 10.1016/j.canlet.2018.03.024. Epub 2018 Mar 21.
CXCR4 surface expression is considered an independent prognostic factor for disease relapse and survival in acute myeloid leukemia (AML) patients. Herein, we investigated targetable autophagy-related mechanisms of CXCR4 for AML therapy. Our experiments show that activation of CXCR4 signaling in AML cells increases autophagic activity and decreases cytarabine-induced apoptosis. Accordingly, combined use of autophagy inhibitors significantly increased the sensitivity of AML cells to cytarabine in vitro and in vivo. Moreover, expression of autophagy-related protein SIRT1 was correlated with SDF-1α-CXCR4 signaling, which interacts with autophagy proteins, such as ATG5 and LC3. Furthermore, in primary human AML samples, high CXCR4 expression was associated with elevated expression levels of SIRT1 and other autophagy-related proteins. Collectively, our data suggest new roles of SDF-1α-CXCR4 signaling on autophagy induction in AML cells, which further promoted their survival under stress. Targeting the SDF-1α-CXCR4-autophagy signaling may contribute to an enhanced efficacy of active treatments.
CXCR4 表面表达被认为是急性髓系白血病（AML）患者疾病复发和生存的独立预后因素。在此，我们研究了 CXCR4 用于 AML 治疗的靶向自噬相关机制。我们的实验表明，AML 细胞中 CXCR4 信号的激活增加了自噬活性，减少了阿糖胞苷诱导的细胞凋亡。因此，在体外和体内，联合使用自噬抑制剂可显著提高 AML 细胞对阿糖胞苷的敏感性。此外，自噬相关蛋白 SIRT1 的表达与 SDF-1α-CXCR4 信号相关，该信号与自噬蛋白（如 ATG5 和 LC3）相互作用。此外，在原发性人 AML 样本中，高 CXCR4 表达与 SIRT1 和其他自噬相关蛋白的表达水平升高相关。总之，我们的数据表明 SDF-1α-CXCR4 信号在 AML 细胞中诱导自噬的新作用，进一步促进了它们在应激下的存活。靶向 SDF-1α-CXCR4-自噬信号可能有助于提高活性治疗的疗效。
