Enhancing low-dose radiotherapy efficacy with PARP inhibitors via FBL-mediated oxidative stress response in colorectal cancer
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.
Authors
- Wenchao Zhao (ORCID: https://orcid.org/0000-0003-3132-3454)
- Zhiyong Mao (ORCID: https://orcid.org/0000-0002-5298-1918)
- Fengbo Tan (ORCID: https://orcid.org/0000-0002-4330-8107)
- Lun‐Quan Sun (ORCID: https://orcid.org/0000-0002-0558-5250)
- Ningbo Wu (ORCID: https://orcid.org/0000-0002-9900-4401)
- Feiyu Tang (ORCID: https://orcid.org/0000-0003-0380-9537)
- Yanfang Qiu (ORCID: https://orcid.org/0000-0003-1995-1327)
- Rong Tan (ORCID: https://orcid.org/0000-0002-3629-8668)
- Anke Geng (ORCID: https://orcid.org/0000-0002-9459-0480)
- Yumei Duan
- Ming Wen (ORCID: https://orcid.org/0000-0001-8081-444X)
- Wenfeng Hu (ORCID: https://orcid.org/0000-0002-2571-3889)
- Meng Wang (ORCID: https://orcid.org/0000-0002-1573-0255)
- Yuqiang Li (ORCID: https://orcid.org/0000-0003-1517-3687)
- Yongwei Zhu (ORCID: https://orcid.org/0000-0001-6911-2471)
- Qian Pei (ORCID: https://orcid.org/0000-0003-4500-0736)
- Haiping Pei (ORCID: https://orcid.org/0000-0002-2480-4738)
- Zhuohang Chen
- Wenzhen Hu
Institutions
- Central South University (CN)
- Hunan University (CN)
- Shanghai Jiao Tong University (CN)
- Hunan Cancer Hospital (CN)
- National Clinical Research (US)
- Shanghai First Maternity and Infant Hospital (CN)
- Xiangya Hospital Central South University (CN)
- Changsha University of Science and Technology (CN)
Publication Details
- Journal
- Oncogene
- Published
- 2024-11-08
- DOI
- https://doi.org/10.1038/s41388-024-03207-w
- Citations
- 5
- Primary Topic
- PARP inhibition in cancer therapy
- Type
- article
- Field-Weighted Citation Impact
- 1.41
Funders
- Bethune Charitable Foundation
- National Natural Science Foundation of China
- Central South University
- Xiangya Hospital, Central South University