Licochalcone A inhibits EGFR signalling and translationally suppresses survivin expression in human cancer cells.
Feng GaoMing LiXinfang YuWenbin LiuLi ZhouWei LiPublished in: Journal of cellular and molecular medicine (2020)
Dysfunction of epidermal growth factor receptor (EGFR) signalling plays a critical role in the oncogenesis of non-small-cell lung cancer (NSCLC). Here, we reported the natural product, licochalcone A, exhibited a profound anti-tumour efficacy through directly targeting EGFR signalling. Licochalcone A inhibited in vitro cell growth, colony formation and in vivo tumour growth of either wild-type (WT) or activating mutation EGFR-expressed NSCLC cells. Licochalcone A bound with L858R single-site mutation, exon 19 deletion, L858R/T790M mutation and WT EGFR ex vivo, and impaired EGFR kinase activity both in vitro and in NSCLC cells. The in silico docking study further indicated that licochalcone A interacted with both WT and mutant EGFRs. Moreover, licochalcone A induced apoptosis and decreased survivin protein robustly in NSCLC cells. Mechanistically, we found that treatment with licochalcone A translationally suppressed survivin through inhibiting EGFR downstream kinases ERK1/2 and Akt. Depletion of the translation initiation complex by eIF4E knockdown effectively inhibited survivin expression. In contrast, knockdown of 4E-BP1 showed the opposite effect and dramatically enhanced survivin protein level. Overall, our data indicate that targeting survivin might be an alternative strategy to sensitize EGFR-targeted therapy.
Keyphrases
- epidermal growth factor receptor
- small cell lung cancer
- induced apoptosis
- advanced non small cell lung cancer
- signaling pathway
- tyrosine kinase
- endoplasmic reticulum stress
- oxidative stress
- brain metastases
- poor prognosis
- pi k akt
- cell cycle arrest
- protein protein
- endothelial cells
- binding protein
- molecular docking
- magnetic resonance imaging
- machine learning
- intellectual disability
- computed tomography
- combination therapy
- deep learning