Metformin reverses 5-FU resistance induced by radiotherapy through mediating folate metabolism in colorectal cancer
Abstract Purpose Radiation therapy has revolutionized the treatment of primary or liver metastases in colorectal cancer (CRC). In colorectal cancer, conventional fractionation (1.8 ~ 2.0 Gy daily) is typically used for treatment. Nevertheless, there is a paucity of research investigating the potenti...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-05-01
|
| Series: | Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s10020-025-01206-5 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Summary: | Abstract Purpose Radiation therapy has revolutionized the treatment of primary or liver metastases in colorectal cancer (CRC). In colorectal cancer, conventional fractionation (1.8 ~ 2.0 Gy daily) is typically used for treatment. Nevertheless, there is a paucity of research investigating the potential implications of radiation therapy-induced alterations in the expression levels of regulatory genes on resistance to chemotherapy agents. Herein, we explored the mechanism by which conventional fractionation drives 5-fluorouracil (5-FU) resistance and metformin (Met) rescued 5-FU resistance in CRC. Methods and materials RNA sequencing, differential genes expression analysis was performed to identify the 5-FU resistance genes after irradiation (according to the convention of cell irradiation, 2 Gy × 8 scheme was selected). Drug sensitivity assay, immunofluorescence staining, folate analogs concentration measurement was used to explore the biological function of histocompatibility minor 13 (HM13) and γ-Glutamyl Hydrolase (GGH). Combined chemosensitivity test and xenograft mouse model has been used to gain insights into the underlying clinical value of the combination of 5-FU and Met. Results The conventional fractionation scheme (2 Gy × 8) induced resistance to 5-FU in the CRC cell line HCT-15, accompanied by an elevated RNA expression level of peptidase HM13. Mechanistically, the increased expression of HM13 caused an abnormal shearing of the N-terminal signal peptide of γ-Glutamyl Hydrolase (GGH), which resulted in decreased intracellular content of 5, 10-methylenetetrahydrofolate (5,10-CH2-THF). Conclusion We revealed a new mechanism of 5-FU resistance induced by irradiated with 2 Gy × 8 through the HM13-GGH-5,10-CH2-THF axis. The synergistic effect of Met and 5-FU can rescue 5-FU resistance after conventional fractionated irradiation. In summary, this work will help to reveal the mechanisms of IR-induced 5-FU resistance, which is important for finding new therapeutic targets and improving the efficacy of chemotherapy regimens after radiotherapy. |
|---|---|
| ISSN: | 1528-3658 |