%0 Journal Article %T c-FLIP promotes drug resistance in non-small-cell lung cancer cells via upregulating FoxM1 expression %A Wang Wen-die %A Shang Yue %A Wang Chen %A Ni Jun %A Wang Ai-min %A Li Gao-jie %A Su Ling %A Chen Shu-zhen %J Acta Pharmacologica Sinica %D 2022 %B 2022 %9 %! c-FLIP promotes drug resistance in non-small-cell lung cancer cells via upregulating FoxM1 expression %K %X 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 ( R 2  = 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. %U http://www.chinaphar.com/article/view/10716 %V 43 %N 11 %P 2956–2966 %@ 1745-7254