Identification of RIBE factors, mechanisms and therapeutic compounds



Radiation-induced bystander effect (RIBE) refers to a unique process, in which factors released by irradiated cells or tissues exert effects on other parts of the animal not exposed to radiation, causing genomic instability, stress responses, and altered apoptosis or cell proliferation. RIBE is a major factor in determining the efficacy and success of radiotherapy in cancer treatment, not only because it affects and causes damage in non-irradiated cells and tissues, leading to various deleterious side effects (e.g. hair loss, fatigue, skin problems, and low blood counts), but also because it can affect irradiated cells through paracrine signaling and cause resistance of cancer cells to radiotherapy. Despite important implications in radioprotection, radiation safety and radiotherapy, the molecular identities of RIBE factors and their mechanisms of action remain elusive. We have used C. elegans as an animal model to study RIBEs and have identified the cysteine protease CPR-4, a homologue of human cathepsin B and a known biomarker for several types of cancer, as the first RIBE factor in nematodes. CPR-4 is secreted from animals irradiated with ultraviolet or ionizing gamma rays and is the major component in the conditioned medium that leads to inhibition of cell death and increased embryonic lethality in unirradiated animals. Moreover, CPR-4 causes these effects and stress response at unexposed sites distal to the irradiated tissue. The activity of CPR-4 is regulated by CEP-1, a homologue of human tumor supprressor gene p53, in response to radiation, and CPR-4 seems to exert RIBEs by acting through the insulin-like growth factor receptor DAF-2. Our study provides critical insights into the elusive RIBE phenomenon, not only on how it is generated and what the RIBE factor is, but also on how the RIBE factor impacts non-irradiated cells. The C. elegans RIBE models that we established will facilitate the identification of additional RIBE factors and underlying mechanisms and will enable screens and development of new drugs that can enhance the efficacy of targeted cell killing, and at the same time, reduce side effects caused by radiotherapy.


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Peng, Y.*, Zhang, M.*, Zheng, L.J.*, Liang,Q.*, Li, H.Z*., Chen, J.T., Guo, H., Yoshina, S. Chen, Y.Z., Zhao, X., Wu, X.Q., Liu, B., Mitani, S., Yu, J.S., and Xue, D. (2017). Cysteine protease cathepsin B mediates radiation-induced bystander effects. Nature 547, 458-462 (Abstract and PDF). *Equal contribution