PRKCSH enhances colorectal cancer radioresistance via IRE1α/XBP1s-mediated DNA repair
Abstract Neoadjuvant radiotherapy is the standard treatment for locally advanced rectal cancer, but resistance to this therapy remains a significant clinical challenge. Understanding the molecular mechanisms of radioresistance and developing strategies to enhance radiosensitivity are crucial for imp...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-04-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07582-4 |
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| author | Hui Shen Jing Jin Nanxi Yu Tingting Liu Yongzhan Nie Zhijie Wan Yuanyuan Chen Kun Cao Ying Xu Yijuan Huang Chao Feng Ruixue Huang Yanyong Yang Fu Gao |
| author_facet | Hui Shen Jing Jin Nanxi Yu Tingting Liu Yongzhan Nie Zhijie Wan Yuanyuan Chen Kun Cao Ying Xu Yijuan Huang Chao Feng Ruixue Huang Yanyong Yang Fu Gao |
| author_sort | Hui Shen |
| collection | DOAJ |
| description | Abstract Neoadjuvant radiotherapy is the standard treatment for locally advanced rectal cancer, but resistance to this therapy remains a significant clinical challenge. Understanding the molecular mechanisms of radioresistance and developing strategies to enhance radiosensitivity are crucial for improving treatment outcomes. This study investigated the role of PRKCSH in colorectal cancer radioresistance and its underlying mechanisms. Our results demonstrate that PRKCSH is upregulated in colorectal cancer cells following ionizing radiation. Inhibiting PRKCSH sensitized these cells to radiation by reducing clonogenic survival, promoting apoptosis, and impairing DNA damage repair. Mechanistically, PRKCSH inhibition reduced p53 ubiquitination and degradation by activating the ER stress IRE1α/XBP1s pathway after radiation exposure, which enhanced DNA repair and contributed to radioresistance. In preclinical CRC models, PRKCSH depletion suppressed tumor growth and increased radiosensitivity. Similarly, in patient-derived organoid models, PRKCSH knockdown reduced organoid growth post-radiotherapy. In rectal cancer patients receiving neoadjuvant radiotherapy, higher PRKCSH expression in post-treatment samples correlated with reduced tumor regression. These findings suggest that targeting PRKCSH diminishes radioresistance by impairing DNA repair through the modulation of ER stress. Furthermore, PRKCSH expression may serve as a biomarker for evaluating radiotherapy efficacy and clinical outcomes in rectal cancer patients undergoing neoadjuvant therapy. |
| format | Article |
| id | doaj-art-fb3d4c1edfbc4561a7d4e0f78f1dda2f |
| institution | DOAJ |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-fb3d4c1edfbc4561a7d4e0f78f1dda2f2025-08-20T03:08:12ZengNature Publishing GroupCell Death and Disease2041-48892025-04-0116111610.1038/s41419-025-07582-4PRKCSH enhances colorectal cancer radioresistance via IRE1α/XBP1s-mediated DNA repairHui Shen0Jing Jin1Nanxi Yu2Tingting Liu3Yongzhan Nie4Zhijie Wan5Yuanyuan Chen6Kun Cao7Ying Xu8Yijuan Huang9Chao Feng10Ruixue Huang11Yanyong Yang12Fu Gao13Department of Radiation Medicine, Faculty of Naval Medicine, Naval Medical UniversityDepartment of Radiation Medicine, Faculty of Naval Medicine, Naval Medical UniversityKey Laboratory of Radiological Protection and Nuclear Emergency, National Institute for Radiological Protection, Chinese Center for Disease Control and PreventionDepartment of Radiation Medicine, Faculty of Naval Medicine, Naval Medical UniversityState Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical UniversityDepartment of Radiation Medicine, Faculty of Naval Medicine, Naval Medical UniversityDepartment of Radiation Medicine, Faculty of Naval Medicine, Naval Medical UniversityDepartment of Radiation Medicine, Faculty of Naval Medicine, Naval Medical UniversityDepartment of Radiation Medicine, Faculty of Naval Medicine, Naval Medical UniversityDepartment of Central Laboratory, Affiliated Hospital of Jiaxing UniversityInstitutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Medical College of Soochow UniversityDepartment of Occupational and Environmental Health, Xiangya School of Public Health, Central South UniversityDepartment of Radiation Medicine, Faculty of Naval Medicine, Naval Medical UniversityDepartment of Radiation Medicine, Faculty of Naval Medicine, Naval Medical UniversityAbstract Neoadjuvant radiotherapy is the standard treatment for locally advanced rectal cancer, but resistance to this therapy remains a significant clinical challenge. Understanding the molecular mechanisms of radioresistance and developing strategies to enhance radiosensitivity are crucial for improving treatment outcomes. This study investigated the role of PRKCSH in colorectal cancer radioresistance and its underlying mechanisms. Our results demonstrate that PRKCSH is upregulated in colorectal cancer cells following ionizing radiation. Inhibiting PRKCSH sensitized these cells to radiation by reducing clonogenic survival, promoting apoptosis, and impairing DNA damage repair. Mechanistically, PRKCSH inhibition reduced p53 ubiquitination and degradation by activating the ER stress IRE1α/XBP1s pathway after radiation exposure, which enhanced DNA repair and contributed to radioresistance. In preclinical CRC models, PRKCSH depletion suppressed tumor growth and increased radiosensitivity. Similarly, in patient-derived organoid models, PRKCSH knockdown reduced organoid growth post-radiotherapy. In rectal cancer patients receiving neoadjuvant radiotherapy, higher PRKCSH expression in post-treatment samples correlated with reduced tumor regression. These findings suggest that targeting PRKCSH diminishes radioresistance by impairing DNA repair through the modulation of ER stress. Furthermore, PRKCSH expression may serve as a biomarker for evaluating radiotherapy efficacy and clinical outcomes in rectal cancer patients undergoing neoadjuvant therapy.https://doi.org/10.1038/s41419-025-07582-4 |
| spellingShingle | Hui Shen Jing Jin Nanxi Yu Tingting Liu Yongzhan Nie Zhijie Wan Yuanyuan Chen Kun Cao Ying Xu Yijuan Huang Chao Feng Ruixue Huang Yanyong Yang Fu Gao PRKCSH enhances colorectal cancer radioresistance via IRE1α/XBP1s-mediated DNA repair Cell Death and Disease |
| title | PRKCSH enhances colorectal cancer radioresistance via IRE1α/XBP1s-mediated DNA repair |
| title_full | PRKCSH enhances colorectal cancer radioresistance via IRE1α/XBP1s-mediated DNA repair |
| title_fullStr | PRKCSH enhances colorectal cancer radioresistance via IRE1α/XBP1s-mediated DNA repair |
| title_full_unstemmed | PRKCSH enhances colorectal cancer radioresistance via IRE1α/XBP1s-mediated DNA repair |
| title_short | PRKCSH enhances colorectal cancer radioresistance via IRE1α/XBP1s-mediated DNA repair |
| title_sort | prkcsh enhances colorectal cancer radioresistance via ire1α xbp1s mediated dna repair |
| url | https://doi.org/10.1038/s41419-025-07582-4 |
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