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TOPK Inhibition Enhances the Sensitivity of Colorectal Cancer Cells to Radiotherapy by Reducing the DNA Damage Response

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Abstract

Objective

Abnormal expression of T-lymphokine-activated killer cell-originated protein kinase (TOPK) was reported to be closely related to the resistance of prostate cancer to radiotherapy and to targeted drug resistance in lung cancer. However, the role of TOPK inhibition in enhancing radiosensitivity of colorectal cancer (CRC) cells is unclear. This study aimed to evaluate the radiosensitization of TOPK knockdown in CRC cells.

Methods

The expression of TOPK was detected in CRC tissues by immunohistochemistry, and the effect of TOPK knockdown was detected in CRC cells by Western blotting. CCK-8 and clonogenic assays were used to detect the growth and clonogenic ability of CRC cells after TOPK knockdown combined with radiotherapy in CRC cells. Furthermore, proteomic analysis showed that the phosphorylation of TOPK downstream proteins changed after radiotherapy. DNA damage was detected by the comet assay. Changes in the DNA damage response signaling pathway were analyzed by Western blotting, and apoptosis was detected by flow cytometry.

Results

The expression of TOPK was significantly greater in CRC tissues at grades 2–4 than in those at grade 1. After irradiation, CRC cells with genetically silenced TOPK had shorter comet tails and reduced expression levels of DNA damage response-associated proteins, including phospho-cyclin-dependent kinase 1 (p-CDK1), phospho-ataxia telangiectasia-mutated (p-ATM), poly ADP-ribose polymerase (PARP), and meiotic recombination 11 homolog 1 (MRE11).

Conclusions

TOPK was overexpressed in patients with moderately to poorly differentiated CRC. Moreover, TOPK knockdown significantly enhanced the radiosensitivity of CRC cells by reducing the DNA damage response.

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Author notes

  1. These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Oncology, The Affiliated Hospital of Guilin Medical University, Guilin, 541001, China

    Shi-gui Pang, **n Zhang, Zhao-xin Li, Li-fei He, Feng Chen, Ming-long Liu & Kong-lan Luo

  2. Cancer Research Institute, The Affiliated Hospital of Guilin Medical University, Guilin, 541001, China

    Ying-ze Huang, Jian-mei Mo & Juan-juan **ao

  3. Translational Medical Center, Huaihe Hospital, Henan University, Kaifeng, 475000, China

    Juan-juan **ao & Feng Zhu

  4. Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, The Affiliated Hospital of Guilin Medical University, Guilin, 541001, China

    Feng Zhu

Authors
  1. Shi-gui Pang
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  2. **n Zhang
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  3. Zhao-xin Li
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  4. Li-fei He
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  10. Juan-juan **ao
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Corresponding authors

Correspondence to Juan-juan **ao or Feng Zhu.

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The authors declare that there is no conflict of interest with any financial organization or corporation or individual that can inappropriately influence this work.

Additional information

This study was supported by the Guangxi Zhuang Autonomous Region Program of China (No. Z-C20220797), Guangxi Science and Technology Planning Project of China (No. Guike AD20297047), and National Natural Science Foundation of China (No. 81902849).

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Pang, Sg., Zhang, X., Li, Zx. et al. TOPK Inhibition Enhances the Sensitivity of Colorectal Cancer Cells to Radiotherapy by Reducing the DNA Damage Response. CURR MED SCI 44, 545–553 (2024). https://doi.org/10.1007/s11596-024-2884-0

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  • DOI: https://doi.org/10.1007/s11596-024-2884-0

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