Purpose: Radiotherapy (RT) is one of the major treatments of cervical cancer. Although the prognosis of clinical cervical cancer becomes better in recent years, some patients still suffer from the recurrence and metastasis. Insufficiency of glucose and oxygen supply could increase the radioresistance of cervical cancer cells through regulating hypoxia-inducible factor 1 (HIF-1) in tumor microenvironment and glucose metabolism. And, berberine can regulate HIF-1. However, how berberine regulates tumor microenvironment and radioresistance through HIF-1 remains to be elucidated.

Materials and methods: The human HeLa cervical cancer cells were treated with berberine and radiation under the high and low concentrations of glucose and oxygen, respectively. The survival of cells was tested by CCK-8 assay and colony formation assay. We investigated the PI3K- and IDH3α-related pathway molecules that may regulate HIF-1α by qPCR and western blot. Differentially expressed genes (DEGs) were identified by integrating five related cohort profile datasets. Protein–protein interaction (PPI) network analyses of DEGs related to HIF-1α were conducted by using the STRING database and Cytoscape software.

Results: Berberine dramatically damaged HeLa cells under hypoxic and low-glucose conditions compared with the normoxic and high-glucose conditions. The clonogenic assay indicated that the application of berberine decreased the number of colony counts compared to the negative control. Low doses of berberine might decrease the level of phospho-PI3K and HIF-1α under the nutrient-deprived conditions. Moreover, we found that most of the differentially expressed genes which were related to CDKN1B were the downstream molecules regulated by HIF-1α.

Conclusion: The results indicated that berberine could dramatically overcome the low-glucose and hypoxia-induced radioresistance. And the regulation berberine on nutrition-deficient conditions might involve in PI3K/HIF-1 pathway. Thus, the interference of glucose metabolism by berberine might be an attractive method to eliminate radioresistant cells and improve radiotherapy efficacy.

目的：放射疗法（RT）是宫颈癌的主要治疗方法之一。尽管近年来临床子宫颈癌的预后变得更好，但是一些患者仍然患有复发和转移。葡萄糖和氧气供应不足可通过调节肿瘤微环境和葡萄糖代谢中的缺氧诱导因子1（HIF-1）来增加子宫颈癌细胞的放射抵抗力。而且，小ber碱可以调节HIF-1。然而，小ber碱如何通过HIF-1调节肿瘤微环境和抗辐射性仍有待阐明。

材料和方法：分别在高和低浓度的葡萄糖和氧气下，用小ber碱和放射线处理人HeLa宫颈癌细胞。通过CCK-8测定和集落形成测定来测试细胞的存活。我们研究了可能通过qPCR和western blot调控HIF-1α的PI3K和IDH3α相关途径分子。通过整合五个相关的队列数据集来鉴定差异表达基因（DEG）。使用STRING数据库和Cytoscape软件对与HIF-1α相关的DEG进行蛋白质-蛋白质相互作用（PPI）网络分析。

结果：与低氧和高葡萄糖条件相比，小ber碱在低氧和低葡萄糖条件下对HeLa细胞的损伤显着。克隆形成试验表明，与阴性对照相比，小碱的应用减少了菌落计数的数量。在营养缺乏的情况下，低剂量的小ber碱可能会降低磷酸-PI3K和HIF-1α的水平。此外，我们发现与CDKN1B相关的大多数差异表达基因是受HIF-1α调控的下游分子。

结论：结果表明，小ber碱可以显着克服低糖和低氧引起的放射抵抗。营养不良条件下的黄连素调节可能与PI3K / HIF-1途径有关。因此，小ber碱对葡萄糖代谢的干扰可能是消除放射线耐药细胞并提高放射治疗功效的有吸引力的方法。