Department of Biology, York University, Toronto, ON, M3J 1P3, Canada.
Cell Death Dis. 2019 Jan 8;10(1):22. doi: 10.1038/s41419-018-1274-6.
There are conflicting reports on the adverse effects of erythropoietin (EPO) for the management of cancer-associated anemia. The recognition that erythropoietin receptors (EPORs) are expressed outside the erythroid lineage and concerns that erythropoiesis-stimulating agents (ESAs) may cause tumors to grow and increase the risk of venous thromboembolism have resulted in substantially fewer cancer patients receiving ESA therapy to manage myelosuppressive chemotherapy. In this study, we found that EPO suppresses p53-dependent apoptosis induced by genotoxic (daunorubicin, doxorubicin, and γ-radiation) and non-genotoxic (nutlin-3a) agents and induces a senescence-like state in myeloid leukemia cells. EPO interferes with stress-dependent Mdm2 downregulation and leads to the destabilization of p53 protein. EPO selectively modulates the expression of p53 target genes in response to DNA damage preventing the induction of a number of noncoding RNAs (ncRNAs) previously associated with p53-dependent apoptosis. EPO also enhances the expression of the cyclin-dependent kinase inhibitor p21 and promotes recruitment of p53 to the p21 promoter. In addition, EPO antagonizes Mcl-1 protein degradation in daunorubicin-treated cells. Hence, EPO signaling targets Mcl-1 expression and the p53-Mdm2 network to promote tumor cell survival.
关于促红细胞生成素（EPO）在癌症相关贫血治疗中的不良反应存在相互矛盾的报告。人们认识到促红细胞生成素受体（EPOR）在外周血谱系之外表达，并且担心促红细胞生成刺激剂（ESA）可能导致肿瘤生长并增加静脉血栓栓塞的风险，这导致接受 ESA 治疗以治疗骨髓抑制性化疗的癌症患者大大减少。在这项研究中，我们发现 EPO 抑制了由遗传毒性（柔红霉素、阿霉素和γ辐射）和非遗传毒性（nutlin-3a）药物诱导的 p53 依赖性细胞凋亡，并诱导髓样白血病细胞进入衰老样状态。EPO 干扰应激依赖性 Mdm2 下调，并导致 p53 蛋白的不稳定。EPO 选择性地调节 p53 靶基因的表达，以响应 DNA 损伤，防止先前与 p53 依赖性细胞凋亡相关的许多非编码 RNA（ncRNA）的诱导。EPO 还增强了周期蛋白依赖性激酶抑制剂 p21 的表达，并促进 p53 募集到 p21 启动子。此外，EPO 在柔红霉素处理的细胞中拮抗 Mcl-1 蛋白降解。因此，EPO 信号转导靶向 Mcl-1 表达和 p53-Mdm2 网络以促进肿瘤细胞存活。
