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Licochalcone A inhibits EGFR signalling and translationally suppresses survivin expression in human cancer cells |
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| Authors: | Feng Gao Ming Li Xinfang Yu Wenbin Liu Li Zhou Wei Li |
| Institution: | 1. Department of Ultrasonography, The Third Xiangya Hospital of Central South University, Changsha, China
Cell Transplantation and Gene Therapy Institute, The 3rd Xiangya Hospital of Central South University, Changsha, China Contribution: Conceptualization (equal), Data curation (equal), Formal analysis (equal), Funding acquisition (equal), Methodology (equal);2. Cell Transplantation and Gene Therapy Institute, The 3rd Xiangya Hospital of Central South University, Changsha, China Changsha Stomatological Hospital, Changsha, China Contribution: Conceptualization (equal), Data curation (equal), Formal analysis (equal), ?Investigation (equal), Methodology (equal);3. Cell Transplantation and Gene Therapy Institute, The 3rd Xiangya Hospital of Central South University, Changsha, China Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA Contribution: Conceptualization (equal), Data curation (equal), Formal analysis (equal), ?Investigation (equal), Methodology (equal);4. Department of Pathology, Hunan Cancer Hospital, Changsha, China Contribution: Data curation (equal), Formal analysis (equal), ?Investigation (equal);5. Department of Pathology, Xiangya Hospital of Central South University, Changsha, China Contribution: Data curation (equal), Formal analysis (equal), ?Investigation (equal);6. Cell Transplantation and Gene Therapy Institute, The 3rd Xiangya Hospital of Central South University, Changsha, China |
| Abstract: | 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. |
| Keywords: | epidermal growth factor receptor licochalcone A non-small-cell lung cancer survivin |