Journal
JCI INSIGHT
Volume 6, Issue 23, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.146334
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Funding
- National Natural Science Foundation of China [81874222, 81672978, 81874233]
- Hubei Natural Science Foundation [2019CFB465]
- National Key Research and Development Program of China [2016YFC0105300, 2019YFC1316204]
- Special Fund for Technological Innovation of Hubei [2020BCA068]
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The study highlights the importance of targeting senescence-like characteristics in cancer-associated fibroblasts to enhance radiosensitivity of non-small cell lung cancer cells, as well as alleviate radiation-induced pulmonary fibrosis.
Cancer cell radioresistance is the primary cause of the decreased curability of non-small cell lung cancer (NSCLC) observed in patients receiving definitive radiotherapy (RT). Following RT, a set of microenvironmental stress responses is triggered, including cell senescence. However, cell senescence is often ignored in designing effective strategies to resolve cancer cell radioresistance. Herein, we identify the senescence-like characteristics of cancer-associated fibroblasts (CAFs) after RT and clarify the formidable ability of senescence-like CAFs in promoting NSCLC cell proliferation and radioresistance through the JAK/STAT pathway. Specific induction of senescence-like CAF apoptosis using FOXO4-DRI, a FOXO4-p53-interfering peptide, resulted in remarkable effects on radiosensitizing NSCLC cells in vitro and in vivo. In addition, in this study, we also uncovered an obvious therapeutic effect of FOXO4-DRI on alleviating radiation-induced pulmonary fibrosis (RIPF) by targeting senescence-like fibroblasts in vivo. In conclusion, by targeting senescence, we offer a strategy that simultaneously decreases radioresistance of NSCLC and the incidence of RIPF.
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