LRTS, UMRE008 Genetic Stability Stem Cells and Radiation, U1274 Inserm, Université de Paris, Université Paris-Saclay, CEA, Paris, Fontenay-aux-Roses, France.
LRIG, UMRE008 Genetic Stability Stem Cells and Radiation, Université de Paris, Université Paris-Saclay, CEA, Paris, Fontenay-aux-Roses, France.
Oncogene. 2021 May;40(19):3460-3469. doi: 10.1038/s41388-021-01746-0. Epub 2021 Mar 25.
In solid cancers, high expression of the cellular prion protein (PrPC) is associated with stemness, invasiveness, and resistance to chemotherapy, but the role of PrPC in tumor response to radiotherapy is unknown. Here, we show that, in neuroblastoma, breast, and colorectal cancer cell lines, PrPC expression is increased after ionizing radiation (IR) and that PrPC deficiency increases radiation sensitivity and decreases radiation-induced radioresistance in tumor cells. In neuroblastoma cells, IR activates ATM that triggers TAK1-dependent phosphorylation of JNK and subsequent activation of the AP-1 transcription factor that ultimately increases PRNP promoter transcriptional activity through an AP-1 binding site in the PRNP promoter. Importantly, we show that this ATM-TAK1-PrPC pathway mediated radioresistance is activated in all tumor cell lines studied and that pharmacological inhibition of TAK1 activity recapitulates the effects of PrPC deficiency. Altogether, these results unveil how tumor cells activate PRNP to acquire resistance to radiotherapy and might have implications for therapeutic targeting of solid tumors radioresistance.
在实体瘤中，细胞朊蛋白 (PrPC) 的高表达与干性、侵袭性和对化疗的耐药性有关，但 PrPC 在肿瘤对放疗的反应中的作用尚不清楚。在这里，我们表明，在神经母细胞瘤、乳腺癌和结直肠癌细胞系中，PrPC 表达在电离辐射 (IR) 后增加，而 PrPC 缺失会增加肿瘤细胞对辐射的敏感性并降低辐射诱导的耐药性。在神经母细胞瘤细胞中，IR 激活 ATM，触发 TAK1 依赖性 JNK 磷酸化，随后激活 AP-1 转录因子，最终通过 PRNP 启动子中的 AP-1 结合位点增加 PRNP 启动子转录活性。重要的是，我们表明，这种 ATM-TAK1-PrPC 途径介导的耐药性在所有研究的肿瘤细胞系中都被激活，并且 TAK1 活性的药理学抑制可再现 PrPC 缺失的作用。总之，这些结果揭示了肿瘤细胞如何激活 PRNP 以获得对放疗的耐药性，这可能对靶向治疗实体瘤耐药性具有重要意义。
