Yu Hui, Aravindan Natarajan, Xu Ji, Natarajan Mohan
Department of Pathology, University of Texas Health Science Center, San Antonio, TX, 78229, USA; Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450001, China.
Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
Cell Signal. 2017 Feb;31:105-111. doi: 10.1016/j.cellsig.2017.01.011. Epub 2017 Jan 6.
Understanding the underlying mechanism by which cancer cells acquire resistance to radiation and favorably selected for its clonal expansion will provide molecular insight into tumor recurrence at the treatment site. In the present study, we investigated the molecular mechanisms prompted in MCF-7 breast cancer cells in response to clinical radiation and the associated coordination of intra- and inter-cellular signaling that orchestrate radio-resistance and tumor relapse/recurrence. Our findings showed that 2 or 10Gy of Cs γ-rays at a dose rate of 1.03Gy/min trigger the activation of nuclear factor kappa B (NF-κB), its DNA-binding activity and recycles its own transcription. NF-κB DNA-binding kinetic analysis demonstrated both sustained and dual phase NF-κB activation with radiation. Gene manipulation approach revealed that radiation triggered NF-κB-mediated TNF-α transcriptional activity. TNF-α blocking approach confirmed that the de novo synthesis and secretion of TNF-α serves as a pre-requisite for the second phase of NF-κB activation and sustained maintenance. Radiation-associated NF-κB-dependent secretion of TNF-α from irradiated cells, in parallel, activates NF-κB in the non-targeted un-irradiated bystander cells. Together, these findings demonstrated that radiation-triggered NF-κB-dependent TNFα secretion is critical for self-sustenance of NF-κB (through autocrine positive feedback signaling) and for coordinating bystander response (through inter-cellular paracrine mechanism) after radiation exposure. Further, the data suggest that this self-sustained NF-κB in the irradiated cells determines radio-resistance, survival advantage and clonal expansion of the tumor cells at the treatment site. Parallel maintenance of NF-ΚB-TNF-α-NF-κB feedback-cycle in the un-irradiated non-targeted bystander cells initiates supportive mechanism for the promotion and progression of surviving tumor cells. Intervening this molecular pathway would help us to achieve disease-free cancer survivors.
了解癌细胞获得辐射抗性并因此被选择进行克隆扩增的潜在机制，将为治疗部位肿瘤复发提供分子层面的见解。在本研究中，我们调查了MCF-7乳腺癌细胞在临床放疗后所引发的分子机制，以及细胞内和细胞间信号传导的相关协同作用，这些协同作用共同调控放射抗性和肿瘤复发。我们的研究结果表明，以1.03Gy/分钟的剂量率给予2或10Gy的铯γ射线，会触发核因子κB（NF-κB）的激活、其DNA结合活性并使其自身转录循环。NF-κB DNA结合动力学分析表明，辐射会导致NF-κB持续且呈双相激活。基因操作方法显示，辐射会触发NF-κB介导的肿瘤坏死因子-α（TNF-α）转录活性。TNF-α阻断方法证实，TNF-α的从头合成和分泌是NF-κB激活第二阶段和持续维持的先决条件。与此同时，受辐射细胞中与辐射相关的NF-κB依赖性TNF-α分泌会激活未受辐射的非靶向旁观者细胞中的NF-κB。这些发现共同表明，辐射触发的NF-κB依赖性TNFα分泌对于NF-κB的自我维持（通过自分泌正反馈信号）以及辐射暴露后协调旁观者反应（通过细胞间旁分泌机制）至关重要。此外，数据表明，受辐射细胞中这种自我维持的NF-κB决定了治疗部位肿瘤细胞的放射抗性、生存优势和克隆扩增。未受辐射的非靶向旁观者细胞中NF-κB-TNF-α-NF-κB反馈循环的平行维持启动了促进存活肿瘤细胞生长和进展的支持机制。干预这一分子途径将有助于我们实现无癌生存。
