Abstract
Glycolysis was reported to have a positive correlation with radioresistance. Our previous study found that the miR-33a functioned as a tumor suppressor in malignant melanoma by targeting hypoxia-inducible factor1-alpha (HIF-1α), a gene known to promote glycolysis. However, the role of miR-33a-5p in radiosensitivity remains to be elucidated. We found that miR-33a-5p was downregulated in melanoma tissues and cells. Cell proliferation was downregulated after overexpression of miR-33a-5p in WM451 cells, accompanied by a decreased level of glycolysis. In contrast, cell proliferation was upregulated after inhibition of miR-33a-5p in WM35 cells, accompanied by increased glycolysis. Overexpression of miR-33a-5p enhanced the sensitivity of melanoma cells to X-radiation by MTT assay, while downregulation of miR-33a-5p had the opposite effects. Finally, in vivo experiments with xenografts in nude mice confirmed that high expression of miR-33a-5p in tumor cells increased radiosensitivity via inhibiting glycolysis. In conclusions, miR-33a-5p promotes radiosensitivity by negatively regulating glycolysis in melanoma.
Highlights
Malignant melanoma (MM), an aggressive skin malignancy, is the fifth most common malignant tumor in men and the seventh most common malignant tumor in women [1, 2]
Our previous study found that the miR-33a functioned as a tumor suppressor in malignant melanoma by targeting hypoxia-inducible factor1-alpha (HIF-1α), a gene known to promote glycolysis
Increasing evidence indicates that microRNAs are associated with tumor radiosensitivity
Summary
Malignant melanoma (MM), an aggressive skin malignancy, is the fifth most common malignant tumor in men and the seventh most common malignant tumor in women [1, 2]. Radiation is an important treatment modality for melanoma, methods of increasing the radiosensitivity of melanoma cells are urgently needed. Increased glucose uptake and accumulation of lactate are common features of cancer cells. Lactate accumulation is considered an early event of malignant tumors and promotes radiation resistance in solid tumors [6]. Aerobic glycolysis generates a chemically reduced milieu associated with the development of radioresistance in cancer cells, suggesting a significant therapeutic gain for combination with glycolysis inhibitors in radiotherapy [6, 8,9,10]. A combination of 2-deoxy-d-glucose and 6-aminonicotinamide (6-AN, an inhibitor of the pentose phosphate pathway) increased the radiosensitivity of neck cancer cells by activating ASK1/JNK/p38 MAPK signaling [13, 14]. Developing effective targeting agents of glycolysis may provide alternative therapeutic strategies for enhancing MM radiosensitivity
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