Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
Cancer Lett. 2021 Oct 10;518:127-139. doi: 10.1016/j.canlet.2021.07.019. Epub 2021 Jul 13.
Radiotherapy is a standard and conventional treatment strategy for nasopharyngeal carcinoma (NPC); however, radioresistance remains refractory to clinical outcomes. Understanding the molecular mechanism of radioresistance is crucial for advancing the efficacy of radiotherapy and improving the prognosis of NPC. In this study, β-lactamase-like-protein 2 (LACTB2) was identified as a potential biomarker for radioresistance using tandem mass tag proteomic analysis of NPC cells, gene chip analysis of NPC tissues, and differential gene analysis between NPC and normal nasopharyngeal tissues from the Gene Expression Omnibus database GSE68799. Meanwhile, LACTB2 levels were elevated in the serum of patients with NPC after radiotherapy. Inhibiting LACTB2 levels and mitophagy can sensitize NPC cells to ionizing radiation. In NPC cells, LACTB2 was augmented at the transcription and protein levels after radiation rather than nucleus-cytoplasm-mitochondria transposition to activate PTEN-induced kinase 1 (PINK1) and mitophagy. In addition, LACTB2 was first authenticated to co-locate with PINK1 by interacting with its N-terminal domain. Together, our findings indicate that overexpressed LACTB2 provoked PINK1-dependent mitophagy to promote radioresistance and thus might serve as a prognostic biomarker for NPC radiotherapy.
放射疗法是鼻咽癌（NPC）的标准和常规治疗策略；然而，放射抵抗仍然难以解决临床结果。了解放射抵抗的分子机制对于提高放射治疗的疗效和改善 NPC 的预后至关重要。在这项研究中，使用串联质谱标签蛋白质组学分析 NPC 细胞、NPC 组织的基因芯片分析以及来自基因表达综合数据库 GSE68799 的 NPC 与正常鼻咽组织之间的差异基因分析，确定β-内酰胺酶样蛋白 2（LACTB2）是 NPC 放射抵抗的潜在生物标志物。同时，放射治疗后 NPC 患者血清中的 LACTB2 水平升高。抑制 LACTB2 水平和自噬可以使 NPC 细胞对电离辐射敏感。在 NPC 细胞中，LACTB2 在转录和蛋白质水平上增加，而不是核质线粒体易位以激活 PTEN 诱导的激酶 1（PINK1）和自噬。此外，LACTB2 首先通过与其 N 端结构域相互作用被确认为与 PINK1 共定位。总之，我们的研究结果表明，过表达的 LACTB2 引发了依赖于 PINK1 的自噬，从而促进了放射抵抗，因此可能成为 NPC 放射治疗的预后生物标志物。
