http://orcid.org/0000-0001-7563-505X
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Abstract
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.
Disclosure statement
The authors declare no conflict of interest.
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Notes on contributors
Xiaozhu Zeng
Xiaozhu Zeng, is a master degree candidate at Chongqing Medical University from 2018 until 2021, Chongqing, China. She performed the experiments, analyzed and integrated of data and wrote the manuscript. She is now focusing on basic research in oncology.
Linghong Wan
Linghong Wan, is a master degree candidate at Chongqing Medical University from 2017 until 2020, Chongqing, China. She carried out acquisition of data. She is now mainly studying clinical research in oncology.
Yu Wang
Yu Wang, MD, PhD is a clinical doctor of Pediatrics at the Southwest Hospital, Army Medical University, Chongqing, China. She facilitated quality assurance of data. Her research interest is hyperoxia damage.
Jinmin Xue
Jinmin Xue, is a master degree candidate at Chongqing Medical University from 2017 until 2020, Chongqing, China. She conducted a part of cell experiments. She is familiar with clinical research in radiation oncology.
Huaju Yang
Huaju Yang, is a master degree candidate at Chongqing Medical University from 2017 until 2020, Chongqing, China. She is involved in bioinformatics analysis. She focuses clinical research in oncology.
Yuxi Zhu
Yuxi Zhu, MD, PhD is a radio-oncologist of the First Affiliated Hospital of Chongqing Medical University, Chongqing, China. He not only designed the study, and also fulfill the initial manuscript and critically revised the final manuscript. His research interest is radioresistance and hypoxia.