Enhancing low-dose radiotherapy efficacy with PARP inhibitors via FBL-mediated oxidative stress response in colorectal cancer.

Autor: Wen M; Department of Oncology, Xiangya Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008, China.; Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha, 410008, China.; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Huan, 410008, China.; Hunan International Science and Technology Collaboration Base of Precision Medicine for Cancer, Changsha, 410008, China.; Center for Molecular Imaging of Central South University, Xiangya Hospital, Changsha, 410008, China., Qiu Y; Department of Oncology, Xiangya Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008, China.; Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha, 410008, China.; Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China., Wang M; Department of Oncology, Xiangya Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008, China.; Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha, 410008, China., Tang F; Department of Oncology, Xiangya Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008, China.; Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha, 410008, China., Hu W; Department of Oncology, Xiangya Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008, China.; Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha, 410008, China., Zhu Y; Hunan International Scientific and Technological Cooperation Base of Brain Tumor Research, Xiangya Hospital, Central South University, Changsha, 410008, China., Zhao W; Department of Oncology, Xiangya Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008, China.; Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha, 410008, China., Hu W; Department of Oncology, Xiangya Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008, China.; Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha, 410008, China., Chen Z; Department of Oncology, Xiangya Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008, China.; Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha, 410008, China., Duan Y; Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China., Geng A; Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China., Tan F; General Surgery Department, Xiangya Hospital, Central South University, Changsha, 410008, China., Li Y; General Surgery Department, Xiangya Hospital, Central South University, Changsha, 410008, China., Pei Q; General Surgery Department, Xiangya Hospital, Central South University, Changsha, 410008, China., Pei H; General Surgery Department, Xiangya Hospital, Central South University, Changsha, 410008, China., Mao Z; Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China., Wu N; Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai JiaoTong University School of Medicine, Shanghai, China., Sun L; Department of Oncology, Xiangya Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008, China. lunquansun@csu.edu.cn.; Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha, 410008, China. lunquansun@csu.edu.cn.; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Huan, 410008, China. lunquansun@csu.edu.cn.; Hunan International Science and Technology Collaboration Base of Precision Medicine for Cancer, Changsha, 410008, China. lunquansun@csu.edu.cn.; Center for Molecular Imaging of Central South University, Xiangya Hospital, Changsha, 410008, China. lunquansun@csu.edu.cn., Tan R; Department of Oncology, Xiangya Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008, China. rongtan@csu.edu.cn.; Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha, 410008, China. rongtan@csu.edu.cn.; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Huan, 410008, China. rongtan@csu.edu.cn.; Hunan International Science and Technology Collaboration Base of Precision Medicine for Cancer, Changsha, 410008, China. rongtan@csu.edu.cn.; Center for Molecular Imaging of Central South University, Xiangya Hospital, Changsha, 410008, China. rongtan@csu.edu.cn.; Hunan key laboratory of aging biology, Xiangya Hospital, Central South University, Changsha, China. rongtan@csu.edu.cn.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2024 Nov 08. Date of Electronic Publication: 2024 Nov 08.
DOI: 10.1038/s41388-024-03207-w
Abstrakt: The effectiveness of radiotherapy in colorectal cancer (CRC) relies on its ability to induce cell death via the generation of reactive oxygen species (ROS). However, genes responsible for mitigating oxidative stress can impede radiotherapy's efficacy. In this study, we elucidate a significant association between the nucleolar protein Fibrillarin (FBL) and the oxidative stress response in CRC tumors. Our findings reveal elevated expression of FBL in colorectal cancer, which positively correlates with oxidative stress levels. Mechanistically, FBL demonstrates direct accumulation at DNA damage sites under the regulation of PARP1. Specifically, the N-terminal GAR domain of FBL is susceptible to PARylation by PARP1, enabling FBL to recognize PARylated proteins. The accumulation of damaged FBL plays a pivotal role in facilitating short-patched base excision repair by recruiting Ligase III and disassociating PCNA and FEN1. Moreover, tumors with heightened FBL expression exhibit reduced DNA damage levels but increased sensitivity to combined low-dose radiotherapy and olaparib treatment. This underscores the potential of leveraging PARP inhibitors to augment radiotherapy sensitivity in CRC cases characterized by elevated FBL expression, offering a promising therapeutic avenue.
(© 2024. The Author(s).)
Databáze: MEDLINE
Externí odkaz: