Ursolic Acid promotes apoptosis and mediates transcriptional suppression of CT45A2 gene expression in NSCLCs harboring EGFR T790M.
Br J Pharmacol. 2019 Jul 19. Epub 2019 Jul 19. PMID: 31322286
BACKGROUND AND PURPOSE: In non-small-cell lung carcinoma (NSCLC) patients, the L858R/T790M mutation of the epithelial growth factor receptor (EGFR) is a major cause of acquired resistance to EGFR-TKIs treatment that limits the therapeutic efficacy. Identification of drugs that can preferentially kill the NSCLC harboring L858R/T790M mutation is therefore critical. In the present study, we evaluated the effects of ursolic acid (UA), an active component isolated from herbal medicine, on erlotinib-resistant H1975 cells that harbor the L858R/T790M mutation.
EXPERIMENTAL APPROACH: Gene expression omnibus (GEO) profiles analyses was applied to detect differentially expressed genes in NSCLC cells harboring EGFR mutation. AnnexinV-FITC/PI, TUNEL staining, MTT, wound healing, RT-PCR, qRT-PCR, western blots, immunostaining, dual-luciferase reporters and ChIP-PCR were utilized to investigate the pharmacological effects of UA in vitro and in vivo.
KEY RESULTS: The cancer/testis antigen family 45 member A2 (CT45A2) was highly expressed in H1975 cells. Ectopic expression of CT45A2 in H1975 cells significantly promotes cell proliferation and motility in vitro. Silencing the CT45A2 expression strongly attenuates H1975 cells motility and growth. The anti-cancer effect of UA is critically dependent on CT45A2 expression in H1975 cells. UA suppressed CT45A2 gene transcription that is mediated by transcriptional factor TCF4 andβ-catenin signaling.
CONCLUSIONS AND IMPLICATIONS: CT45A2 is a novel oncogene for NSCLC with an EGFR T790 mutation. Moreover, UA significantly induces apoptosis and inhibits the proliferation of H1975 cells by negatively regulating theβ-catenin/TCF4/CT45A2 signaling pathway. Therefore, UA may be a potential candidate for NSCLC harboring EGFR-L858R/T790M mutation therapy.