Targeting senescence-like fibroblasts radiosensitizes non–small cell lung cancer and reduces radiation-induced pulmonary fibrosis
Jingshu Meng, … , Honglin Jin, Kunyu Yang
Jingshu Meng, … , Honglin Jin, Kunyu Yang
Published December 8, 2021
Citation Information: JCI Insight. 2021;6(23):e146334. https://doi.org/10.1172/jci.insight.146334.
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Research Article Oncology

Targeting senescence-like fibroblasts radiosensitizes non–small cell lung cancer and reduces radiation-induced pulmonary fibrosis

Abstract

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.

Authors

Jingshu Meng, Yan Li, Chao Wan, Yajie Sun, Xiaomeng Dai, Jing Huang, Yan Hu, Yanan Gao, Bian Wu, Zhanjie Zhang, Ke Jiang, Shuangbing Xu, Jonathan F. Lovell, Yu Hu, Gang Wu, Honglin Jin, Kunyu Yang

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Figure 3

FOXO4-DRI reverses NSCLC cells radioresistance by targeting SL-CAFs.

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FOXO4-DRI reverses NSCLC cells radioresistance by targeting SL-CAFs. (A)...
(A) Representative images of FOXO4 expression in CAFs and SL-CAFs detected by immunofluorescence staining. Scale bar: 100 μm. (B) Western blot for nuclear and total protein expression levels of FOXO4 in CAFs and SL-CAFs. (C) Cell viability assay of CAFs and SL-CAFs treated with different concentrations of FOXO4-DRI for 72 hours. The selectivity index (SI50) represents the differences of IC50 between the 2 groups by nonregression analysis. The indicated results represent the mean ± SEM of 3 independent experiments. (D) The senescence-associated gene expression changes of SL-CAFs incubated with FOXO4-DRI (50 μM) detected by Western blot. (E) H292 cell apoptosis rates after 8 Gy IR detected by flow cytometry and quantitative data of the apoptosis rates as indicated in different groups. The indicated results represent the mean ± SEM of 3 independent experiments, analyzed by 1-way ANOVA. (F) Representative images of colony formation in H292 cells cultured in different media after 0 Gy or 8 Gy IR, and statistically clonogenic survival fraction of H292 cells with different media after 8 Gy IR, determined by clone formation. The indicated results represent the mean ± SEM of 3 independent experiments, analyzed by 1-way ANOVA. (G) The cell viability of H292 determined 72 hours after 8 Gy IR and normalized to non-IR cells as indicated in different groups. The indicated results represent the mean ± SEM of 3 independent experiments. *P < 0.05; **P < 0.01; ***P < 0.001. SL-CAFs, senescence-like CAFs. DRI-CAFs, senescence-like CAFs incubated with FOXO4-DRI.