Vitamin D sensitizes cervical cancer to radiation-induced apoptosis by inhibiting autophagy through degradation of Ambra1.

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.