The forkhead box M1(FoxM1)protein,a transcription factor,plays critical roles in regulating tumor growth and drug resistance,while cellular FLICE-inhibitory protein(c-FLIP),an anti-apoptotic regulator,is involved in the ubiquitin-proteasome pathway.In this study,we investigated the effects of c-FLIP on the expression and ubiquitination levels of FoxM1 along with drug susceptibility in non-small-cell lung cancer(NSCLC)cells.We first showed that the expression levels of FoxM1 and c-FLIP were increased and positively correlated(R2=0.1106,P＜0.0001)in 90 NSCLC samples.The survival data from prognostic analysis demonstrated that high expression of c-FLIP and/or FoxM1 was related to poor prognosis in NSCLC patients and that the combination of FoxM1 and c-FLIP could be a more precise prognostic biomarker than either alone.Then,we explored the functions of c-FLIP/FoxM1 in drug resistance in NSCLC cell lines and a xenograft mouse model in vivo.We showed that c-FLIP stabilized FoxM1 by inhibiting its ubiquitination,thus upregulated the expression of FoxM1 at post-transcriptional level.In addition,a positive feedback loop composed of FoxM1,β-catenin and p65 also participated in c-FLIP-FoxM1 axis.We revealed that c-FLIP promoted the resistance of NSCLC cells to thiostrepton and osimertinib by upregulating FoxM1.Taken together,these results reveal a new mechanism by which c-FLIP regulates FoxM1 and the function of this interaction in the development of thiostrepton and osimertinib resistance.This study provides experimental evidence for the potential therapeutic benefit of targeting the c-FLIP-FoxM1 axis for lung cancer treatment.

Wen-die Wang;Yue Shang;Chen Wang;Jun Ni;Ai-min Wang;Gao-jie Li;Ling Su;Shu-zhen Chen

Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China;School of Life Sciences,Shandong University,Jinan 250100,China

中国药理学报（英文版）

[1]Wen-die Wang;Yue Shang;Chen Wang;Jun Ni;Ai-min Wang;Gao-jie Li;Ling Su;Shu-zhen Chen-.c-FLIP promotes drug resistance in non-small-cell lung cancer cells via upregulating FoxM1 expression)[J].中国药理学报（英文版）,2022(11):2956-2966

thiostrepton,osimertinib

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