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

  • Acta Pharmacol Sin. 2022 Apr 14. doi: 10.1038/s41401-022-00905-7.
Wen-Die Wang  1 ,  Yue Shang  1 ,  Chen Wang  1 ,  Jun Ni  1 ,  Ai-Min Wang  1 ,  Gao-Jie Li  1 ,  Ling Su  2 ,  Shu-Zhen Chen  3
Affiliations
  • 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.
  • 3. Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. [email protected].
PMID: 35422085 DOI: 10.1038/s41401-022-00905-7
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.

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