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AKR1C4 regulates the sensitivity of colorectal cancer cells to chemotherapy through ferroptosis modulation

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Abstract

Purpose

Colorectal cancer (CRC) remains a major global health concern, necessitating innovative therapeutic strategies to enhance treatment efficacy. In this study, we investigated the role of AKR1C4 in CRC and its impact on chemotherapy response.

Methods

AKR1C4 stable knockout CRC cell lines were generated using CRISPR/Cas9 technology. The impact of AKR1C4 depletion on chemotherapy sensitivity was assessed using Sulforhodamine B assay. Long-term, low-dose drug induction with increasing concentrations of 5FU, irinotecan, and oxaliplatin were employed to establish acquired chemoresistant CRC cell lines. Ferroptosis induction and inhibition were examined through total iron content and lipid peroxidation measurements.

Results

We found that AKR1C4 knockout enhances CRC cell sensitivity to chemotherapy, specifically by inducing ferroptosis. The enzymatic activity of AKR1C4 is crucial for regulating chemotherapy sensitivity in CRC cells, as evidenced by the inability of a Y55A mutant to reverse the sensitizing effect. Additionally, AKR1C4 inhibitors enhance chemotherapy sensitivity by inducing ferroptosis. Notably, AKR1C4 depletion resensitizes the acquired chemoresistant CRC cells to chemotherapy, suggesting its potential as a therapeutic target for overcoming acquired chemoresistance. Clinical analysis reveals that high AKR1C4 expression is associated with poor prognosis in CRC patients undergoing chemotherapy, highlighting its significance as a prognostic marker and a potential target for therapeutic intervention.

Conclusion

This study illuminates the multifaceted role of AKR1C4 in CRC, demonstrating its significance in regulating chemotherapy sensitivity, overcoming acquired resistance, and impacting clinical outcomes. The insights provided may pave the way for novel therapeutic strategies in CRC management.

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Data availability

The transcriptomic data for normal colorectal and CRC samples were obtained from TCGA database under the project ID: TCGA-COAD. The dataset is publicly accessible, and researchers can retrieve the information for further analyses from the TCGA data portal (https://portal.gdc.cancer.gov/).

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Funding

This study was funded by “Basic Medicine Special Fund Project” at Qixia City People’s Hospital (Grant no. BMSFP2022066).

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Authors and Affiliations

  1. Department of Gastrointestinal Surgery, Yantaishan Hospital, Yantai, Shandong, China

    Li Wang

  2. Department of Gastroenterology, Qixia City People’s Hospital, Qixia, Shandong, China

    Cuiling Lv & Xiaoxia Liu

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  1. Li Wang
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  3. Xiaoxia Liu
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Contributions

Conceptualization: Li Wang, Cuiling Lv, and Xiaoxia Liu; Resources: Cuiling Lv, Xiaoxia Liu; Data curation: Xiaoxia Liu; Formal Analysis: Li Wang and Xiaoxia Liu; Supervision: Xiaoxia Liu; Validation: Li Wang, Cuiling Lv, and Xiaoxia Liu; Investigation: Li Wang and Xiaoxia Liu; Visualization: Xiaoxia Liu; Methodology: Li Wang, Cuiling Lv, and Xiaoxia Liu; Project administration: Xiaoxia Liu; Writing – original draft: Li Wang; Writing – review & editing: Li Wang, Cuiling Lv, and Xiaoxia Liu.

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Correspondence to Xiaoxia Liu.

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Wang, L., Lv, C. & Liu, X. AKR1C4 regulates the sensitivity of colorectal cancer cells to chemotherapy through ferroptosis modulation. Cancer Chemother Pharmacol (2024). https://doi.org/10.1007/s00280-024-04685-1

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