Abstract
Met proto-oncogene (MET) amplification and tyrosine-protein kinase Met (c-Met) overexpression confer gefitinib resistance in non-small cell lung cancer (NSCLC). The natural product Licochalcone A (Lico A) exhibits a broad range of inhibitory effects against various tumors. However, the effects of Lico A on c-Met signaling and gefitinib resistance in NSCLC remain unclear. In the present study, Lico A efficiently overcame gefitinib-acquired resistance in NSCLC cells by suppressing c-Met signaling. Lico A decreased cell viability and colony formation dose-dependently and impaired in vivo tumorigenesis of gefitinib-resistant HCC827 and PC-9 cells. Furthermore, Lico A induced intrinsic apoptosis and upregulated the protein expression levels of cleaved poly (ADP-ribose) polymerase and cleaved caspase 3. Lico A promoted the interaction between c-Met and E3 ligase c-Casitas B-lineage lymphoma (Cbl), which enhanced c-Cbl-mediated c-Met ubiquitination and degradation. Depletion of c-Cbl compromised Lico A-induced c-Met ubiquitination and its inhibitory efficacy in gefitinib-resistant NSCLC cells. Taken together, the results suggest that Lico A is a promising antitumor agent that might be used to overcome c-Met overexpression-mediated gefitinib resistance in NSCLC cells.
Highlights
Non-small cell lung cancer (NSCLC) is a profoundly devastating disease that is the leading cause of cancer-associated deaths worldwide [1]
Targetable genomic alterations in NSCLC have been examined as attractive therapeutic targets, including those occurring at epidermal growth factor receptor (EGFR), Kirsten rat sarcoma virus (KRAS), anaplastic lymphoma kinase (ALK), and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), and those that lead to altered production of reactive oxygen species [3–5]
These results indicated that Licochalcone A (Lico A) attenuated the activation of c-Met signaling in gefitinib-resistant NSCLC cells
Summary
Non-small cell lung cancer (NSCLC) is a profoundly devastating disease that is the leading cause of cancer-associated deaths worldwide [1]. The acquired resistance to EGFR TKIs, gefitinib, and erlotinib remains a significant challenge [10, 11]. Resistance to EGFR TKIs can be acquired due to secondary mutations. The most common secondary mutation is the EGFR T790M mutation.The aberrant activation of tyrosine-protein kinase Met (c-Met) signaling is an EGFR-independent mechanism that confers EGFR TKIs resistance to the NSCLC cells. Identifying novel antitumor agents targeting c-Met signaling may provide alternative therapeutic approaches to overcome resistance to EGFR-TKIs [15]. The antitumor effects of Lico A have been documented in various types of tumors, including gastric, [18] prostate, [19] ovarian, [20] liver [21], and lung cancers [16, 22]. The effects of Lico A on c-Met signaling and gefitinib resistance have not been fully elucidated. The potential of this compound to overcome gefitinib resistance was assessed in the NSCLC cells
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