c-FLIP promotes drug resistance in non-small-cell lung cancer cells via upregulating FoxM1 expression

Wen-die Wang1, Yue Shang1, Chen Wang1, Jun Ni1, Ai-min Wang1, Gao-jie Li1, Ling Su2, Shu-zhen Chen1
1 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
2 School of Life Sciences, Shandong University, Jinan 250100, China
Correspondence to: Shu-zhen Chen:,
DOI: 10.1038/s41401-022-00905-7
Received: 20 October 2021
Accepted: 27 March 2022
Advance online: 14 April 2022


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.

Keywords: non-small-cell lung cancer; c-FLIP; FoxM1; ubiquitination; thiostrepton; osimertinib

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