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

	author = {Wen-die Wang and Yue Shang and Chen Wang and Jun Ni and Ai-min Wang and Gao-jie Li and Ling Su and Shu-zhen Chen},
	title = {c-FLIP promotes drug resistance in non-small-cell lung cancer cells via upregulating FoxM1 expression},
	journal = {Acta Pharmacologica Sinica},
	volume = {43},
	number = {11},
	year = {2022},
	keywords = {},
	abstract = {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.},
	issn = {1745-7254},	url = {}