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Targeting FBXO22 enhances radiosensitivity in non-small cell lung cancer by inhibiting the FOXM1/Rad51 axis
Yunshang Chen1,2,3, Yun Zhou4, Xue Feng5
1Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Abstract:
Radioresistance is a major constraint on the efficacy of lung cancer radiotherapy, but its mechanism has not been fully elucidated. Here, we found that FBXO22 was aberrantly highly expressed in lung cancer and that FBXO22 knockdown increased the radiosensitivity of lung cancer cells. Mechanistically, FBXO22 promoted Rad51 gene transcription by increasing the level of FOXM1 at the Rad51 promoter, thereby inducing the formation of lung cancer radioresistance. Furthermore, we found that deguelin, a potential inhibitor of FBXO22, enhanced radiosensitivity in an FBXO22/Rad51-dependent manner and was safely tolerated in vivo. Collectively, our results illustrate that FBXO22 induces lung cancer radioresistance by activating the FOXM1/Rad51 axis and provide preclinical evidence for the clinical translation of this critical target.
Insights
Lung cancer radioresistance is reduced by targeting FBXO22, a protein that promotes resistance by activating the FOXM1/Rad51 pathway. Deguelin, an FBXO22 inhibitor, enhances radiosensitivity and is well-tolerated in vivo.
Area of Science:
- Oncology
- Molecular Biology
- Radiotherapy Research
Background:
- Radioresistance significantly limits the effectiveness of lung cancer radiotherapy.
- The precise molecular mechanisms underlying lung cancer radioresistance remain incompletely understood.
Purpose of the Study:
- To investigate the role of FBXO22 in lung cancer radioresistance.
- To elucidate the molecular pathway through which FBXO22 confers radioresistance.
- To evaluate the therapeutic potential of targeting FBXO22 in lung cancer.
Main Methods:
- FBXO22 expression analysis in lung cancer tissues.
- FBXO22 knockdown experiments in lung cancer cell lines.
- Analysis of FOXM1 and Rad51 interactions and gene transcription.
- In vivo studies using deguelin as an FBXO22 inhibitor.
Main Results:
- FBXO22 was found to be highly expressed in lung cancer.
- FBXO22 knockdown significantly increased the radiosensitivity of lung cancer cells.
- FBXO22 enhances Rad51 transcription by increasing FOXM1 levels at the Rad51 promoter.
- Deguelin, an FBXO22 inhibitor, improved radiosensitivity in an FBXO22/Rad51-dependent manner and demonstrated good in vivo tolerability.
Conclusions:
- FBXO22 drives lung cancer radioresistance by activating the FOXM1/Rad51 signaling axis.
- Targeting FBXO22 presents a promising therapeutic strategy to overcome radioresistance in lung cancer.
- Deguelin shows potential as a clinical agent to enhance radiotherapy efficacy in lung cancer patients.
