Cancer-associated fibroblasts facilitate DNA damage repair by promoting the glycolysis in non-small cell lung cancer

Radiotherapy is an essential treatment modality for the management of non-small cell lung cancer (NSCLC) patients. Tumor radioresistance is the major factor limiting the efficacy of radiotherapy in NSCLC patients. Our study aimed to reveal whether cancer-associated fibroblasts (CAFs), one main compo...

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Veröffentlicht in:Biochimica et biophysica acta. Molecular basis of disease 2023-06, Vol.1869 (5), p.166670-166670, Article 166670
Hauptverfasser: Zhang, Hongfang, Zhang, Ke, Qiu, Liqing, Yue, Jing, Jiang, Hong, Deng, Qinghua, Zhou, Rongjing, Yin, Zihao, Ma, Shenglin, Ke, Yuehai
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Sprache:eng
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Zusammenfassung:Radiotherapy is an essential treatment modality for the management of non-small cell lung cancer (NSCLC) patients. Tumor radioresistance is the major factor limiting the efficacy of radiotherapy in NSCLC patients. Our study aimed to reveal whether cancer-associated fibroblasts (CAFs), one main component of the tumor microenvironment, regulated DNA damage response of NSCLC cells following irradiation and clarify the involved mechanisms. We found CAFs inhibited irradiation-induced DNA damage while promoted DNA repair of NSCLC cells and caused cell cycle arrest in the radioresistant S phase. CAFs have the ability of up-regulating and stabilizing c-Myc, leading to the transcription activation of HK2 kinase, a key rate-limiting enzyme in glycolysis by activating Wnt/β-catenin pathway. Attenuation of glycolysis significantly reversed the effect of CAFs on DNA damage response of NSCLC cells. By high-throughput screening of human cytokines/chemokines array, we found CAFs-secreted midkine led to the promotion of glycolysis by activating Wnt/β-catenin pathway in NSCLC cells. In vivo, CAFs caused the radioresistance of NSCLC cells also by promoting the glycolysis in a β-catenin signaling-dependent manner. These findings may provide novel strategies for reversing the radioresistance of NSCLC cells. •CAFs regulate DNA damage response of NSCLC cells by promoting glycolysis.•Inhibition of glycolysis reversed CAFs-induced radioresistance of NSCLC cells.•CAFs promote the glycolysis of NSCLC cells by secreting midkine.•CAFs-secreted midkine initiates the activation of β-catenin/c-myc/HK2 signaling axis.
ISSN:0925-4439
1879-260X
DOI:10.1016/j.bbadis.2023.166670