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Mitochondrial Deoxyguanosine Kinase Induces 5-Fluorouracil Chemotherapy Sensitivity through Autophagy
Lu Dong1,2, Sifan Liu2, Wenjing Sun1,2
1School of Clinical Medicine, Shandong Second Medical University, Weifang, 261000, China.
Aims:
The purpose of this study was to investigate the role of DGUOK in the progression of colorectal cancer (CRC) and its impact on the sensitivity of CRC cells to 5-FU treatment.
Methods:
We conducted bioinformatics analysis and qRT-PCR to evaluate DGUOK expression in CRC tissues/cells. Cell viability of CRC cells treated with 5-FU was assessed using CCK-8 and colony formation assays. Autophagy levels were determined through immunofluorescence assays and Western blot analysis. Additionally, the influence of p-p38 on autophagy was investigated via Western blotting. A rescue assay was performed to confirm whether DGUOK/p38 affects 5-FU sensitivity in CRC cells through autophagy.
Results:
Our findings indicate that DGUOK is upregulated in CRC tissues compared to normal tissues, correlating with increased cell proliferation and migration. Functionally, inhibition of DGUOK enhances autophagy, thereby decreasing the sensitivity of CRC cells to 5-FU. This effect is partly mediated by DGUOK's impact on the mitogen-activated protein kinase (MAPK) pathway, specifically promoting the phosphorylation of p38 MAPK, a crucial regulator in autophagy pathways.
Conclusion:
These results suggest that DGUOK could serve as a novel marker for predicting the efficacy of 5-FU in CRC treatment.
Insights
Deoxyguanosine kinase (DGUOK) is elevated in colorectal cancer (CRC), promoting tumor growth. Inhibiting DGUOK increases autophagy, reducing 5-FU drug sensitivity in CRC cells.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Colorectal cancer (CRC) remains a significant global health challenge.
- 5-fluorouracil (5-FU) is a cornerstone chemotherapy for CRC, but drug resistance limits its efficacy.
- Understanding novel molecular mechanisms influencing CRC progression and drug response is crucial.
Purpose of the Study:
- To investigate the role of deoxyguanosine kinase (DGUOK) in colorectal cancer (CRC) development.
- To determine the impact of DGUOK on the sensitivity of CRC cells to 5-fluorouracil (5-FU) chemotherapy.
- To elucidate the molecular pathways, including autophagy and MAPK signaling, modulated by DGUOK in CRC.
Main Methods:
- Bioinformatics analysis and quantitative real-time PCR (qRT-PCR) were used to assess DGUOK expression in CRC tissues and cell lines.
- Cell viability and colony formation assays evaluated the effects of 5-FU treatment on CRC cells.
- Immunofluorescence and Western blot analyses were employed to measure autophagy levels and p38 MAPK phosphorylation.
- Rescue assays confirmed the involvement of the DGUOK/p38/autophagy axis in 5-FU resistance.
Main Results:
- DGUOK expression was significantly upregulated in CRC tissues compared to normal tissues, correlating with enhanced cell proliferation and migration.
- Inhibition of DGUOK led to increased autophagy and decreased sensitivity of CRC cells to 5-FU.
- DGUOK was found to promote p38 mitogen-activated protein kinase (MAPK) phosphorylation, a key regulator of autophagy.
Conclusions:
- DGUOK plays a critical role in colorectal cancer progression and influences sensitivity to 5-FU chemotherapy.
- The DGUOK-mediated regulation of autophagy via the p38 MAPK pathway contributes to 5-FU resistance in CRC.
- DGUOK emerges as a potential predictive biomarker for 5-FU treatment efficacy in colorectal cancer patients.
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