Laboratory of Molecular Oncology, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.
German Cancer Consortium (DKTK), Partner site University Hospital Essen, Essen, Germany.
Cell Death Dis. 2022 Jun 6;13(6):529. doi: 10.1038/s41419-022-04978-4.
Radiotherapy is an important modality in lung cancer treatment. Despite advances in treatment planning and dose delivery, patient benefit is still limited by in-field relapse and metastatic recurrence. Simultaneous application of cisplatinum-based chemotherapy leads to moderately improved outcomes, thus providing proof-of-concept for radiosensitization strategies in lung cancer. In an unbiased functional genetic screen for radiosensitization targets in lung cancer, we identified syntaxin 18, a protein involved in retrograde vesicular transport between the Golgi apparatus and endoplasmic reticulum, as mediator of radioresistance. Downregulation of endogenous syntaxin 18 specifically reduced clonogenic survival of radioresistant and radiosensitive lung cancer cells following X-radiation. Gene expression programs regulating DNA repair, mitotic checkpoints and mitosis were altered in isogenic cells with reduced syntaxin 18 expression. Functionally, this translated into impaired DNA damage-induced cell cycle checkpoints leading to cell death by mitotic catastrophe. Interestingly, downregulation of syntaxin 18 in lung cancer cells also impaired expression of markers of epithelial-mesenchymal-transition, and reduced migration and invasion capacity. These findings suggest that syntaxin 18 is a key player regulating genes responsible for controlling the growth of the primary tumor as well as metastases upon radiotherapy of lung cancer. They provide a promising lead for biologically rational radiosensitization strategies impacting on radiation-induced cell death as well as metastasis.
放射疗法是肺癌治疗的一种重要手段。尽管在治疗计划和剂量传递方面取得了进展，但患者的受益仍然受到场内复发和转移性复发的限制。顺铂为基础的化疗的同时应用导致适度改善的结果，从而为肺癌的放射增敏策略提供了概念验证。在肺癌放射增敏靶点的无偏功能遗传筛选中，我们发现了参与高尔基体和内质网之间逆行囊泡运输的蛋白质 syntaxin 18，它是放射抵抗的介质。内源性 syntaxin 18 的下调特异性降低了 X 射线照射后耐辐射和敏感的肺癌细胞的集落形成存活能力。在 syntaxin 18 表达降低的同基因细胞中，调节 DNA 修复、有丝分裂检查点和有丝分裂的基因表达程序发生改变。功能上，这转化为受损的 DNA 损伤诱导的细胞周期检查点，导致有丝分裂灾难导致细胞死亡。有趣的是，肺癌细胞中 syntaxin 18 的下调也削弱了上皮-间充质转化标志物的表达，并降低了迁移和侵袭能力。这些发现表明，syntaxin 18 是调节控制原发性肿瘤生长以及肺癌放射治疗后转移的基因的关键因素。它们为影响放射诱导细胞死亡和转移的基于生物学合理性的放射增敏策略提供了有希望的线索。
