Zhang Zhaoming, Yu Xinyue, Cheng Guanghui
Department of Radiation Oncology, China-Japan Union Hospital of Jilin University, Changchun, China.
Cell Death Discov. 2025 Jan 4;11(1):1. doi: 10.1038/s41420-024-02279-7.
Cervical cancer (CC) is becoming a major health issue globally, and radiotherapy plays a crucial role in its treatment. However, the prognosis of some patients remains poor due to tumor resistance to the therapy. This study aimed to explore whether vitamin D could confer a more radiosensitive phenotype in CC based on our previous findings and detection using the database. We found that vitamin D sensitized vitamin D receptor (VDR)-positive CC cells (Siha and Caski) to the cytotoxic effects of radiation in vivo and in vitro. We examined conventional radiation-induced cell death, such as DNA damage and cell cycle arrest, in vitamin D-treated cells to detect the underlying mechanism, but no association was observed between them. Subsequently, our proteome analysis exhibited that autophagy was reduced in irradiated CCs treated with vitamin D, and apoptosis displayed the opposite effect. Moreover, we confirmed that vitamin D-pretreated irradiated cells displayed reduced autophagy activity mediated by the Ambra1 downregulation, and the elevation of apoptosis was attributed to the activation of caspase 8. Importantly, the pharmacological inhibition of caspases or the Ambra1 overexpression could restore tumor proliferation under the vitamin D and radiation combination treatment. Hence, the aforementioned findings revealed the essential impact of vitamin D in terms of enhancing radiosensitivity in CC meditated by inhibiting autophagy and proposed the addition of vitamin D as a viable strategy to improve the therapeutic efficacy of VDR-positive CC.
宫颈癌（CC）正成为全球主要的健康问题，放射治疗在其治疗中起着关键作用。然而，由于肿瘤对该疗法具有抗性，一些患者的预后仍然很差。基于我们之前的研究结果并使用数据库进行检测，本研究旨在探讨维生素D是否能使CC具有更放射敏感的表型。我们发现维生素D在体内和体外使维生素D受体（VDR）阳性的CC细胞（Siha和Caski）对辐射的细胞毒性作用敏感。我们检测了维生素D处理的细胞中常规辐射诱导的细胞死亡，如DNA损伤和细胞周期停滞，以检测潜在机制，但未观察到它们之间的关联。随后，我们的蛋白质组分析显示，在用维生素D处理的受辐射CC中自噬减少，而凋亡则呈现相反的效果。此外，我们证实，维生素D预处理的受辐射细胞表现出由Ambra1下调介导的自噬活性降低，而凋亡的增加归因于半胱天冬酶8的激活。重要的是，在维生素D和辐射联合治疗下，对半胱天冬酶的药理学抑制或Ambra1的过表达可恢复肿瘤增殖。因此，上述发现揭示了维生素D在通过抑制自噬增强CC放射敏感性方面的重要影响，并提出添加维生素D作为提高VDR阳性CC治疗效果的可行策略。
