4.7 Article

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

Journal

ACTA PHARMACOLOGICA SINICA
Volume 43, Issue 11, Pages 2956-2966

Publisher

NATURE PUBL GROUP
DOI: 10.1038/s41401-022-00905-7

Keywords

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

Funding

  1. National Natural Science Foundation of China [81702934]
  2. CAMS Innovation Fund for Medical Sciences (CIFMS) [2019-I2M-1-003, 2021-I2M-1-030]
  3. Beijing Natural Science Foundation [7202132, 7192041]

Ask authors/readers for more resources

This study investigated the effects of c-FLIP on the expression and ubiquitination levels of FoxM1 in non-small-cell lung cancer (NSCLC) cells, and explored the role of c-FLIP/FoxM1 in drug resistance. The findings demonstrated that c-FLIP stabilized FoxM1 by inhibiting its ubiquitination, and promoted the resistance of NSCLC cells to thiostrepton and osimertinib by upregulating FoxM1. The combination of FoxM1 and c-FLIP was found to be a more accurate prognostic biomarker for NSCLC patients.
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, beta-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.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.7
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available