l-2-Hydroxyglutarate contributes to tumor radioresistance through regulating the hypoxia-inducible factor-1α signaling pathway.
Manman ZhangYingshuang LiuXinran LuLiqing DuNingning HeHuijuan SongJinhan WangYeqing GuMengmeng YangChang XuYan WangKaihua JiQiang LiuPublished in: Journal of cellular physiology (2024)
l-2-Hydroxyglutarate (l-2-HG) has been regarded as a tumor metabolite, and it plays a crucial role in adaptation of tumor cells to hypoxic conditions. However, the role of l-2-HG in tumor radioresistance and the underlying mechanism have not yet been revealed. Here, we found that l-2-HG exhibited to have radioresistance effect on U87 human glioblastoma cells, which could reduce DNA damage and apoptosis caused by irradiation, promote cell proliferation and migration, and impair G2/M phase arrest. Mechanistically, l-2-HG upregulated the protein level of hypoxia-inducible factor-1α (HIF-1α) and the expression levels of HIF-1α downstream target genes. The knockdown of l-2-hydroxyglutarate dehydrogenase (L2HGDH) gene promoted the tumor growth and proliferation of U87 cells in nude mice by increasing HIF-1α expression level in vivo. In addition, the low expression level of L2HGDH gene was correlated with the short survival of patients with glioma or kidney cancer. In conclusion, our study revealed the role and mechanism of l-2-HG in tumor radioresistance and may provide a new perspective for overcoming tumor radioresistance and broaden our comprehension of the role of metabolites in tumor microenvironment.
Keyphrases
- induced apoptosis
- cell cycle arrest
- signaling pathway
- dna damage
- poor prognosis
- endothelial cells
- fluorescent probe
- oxidative stress
- genome wide
- endoplasmic reticulum stress
- single cell
- cell death
- binding protein
- cancer stem cells
- pi k akt
- stem cells
- metabolic syndrome
- dna methylation
- radiation therapy
- epithelial mesenchymal transition
- gene expression
- type diabetes
- ms ms
- cell therapy
- insulin resistance
- mesenchymal stem cells
- free survival
- lymph node metastasis