Ursolic acid promotes apoptosis and mediates transcriptional suppression of CT45A2 gene expression in non‐small‐cell lung carcinoma harbouring EGFR T790M mutations

Abstract

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 their therapeutic efficacy. Identification of drugs that can preferentially kill the NSCLC harbouring L858R/T790M mutation is therefore critical. Here, we have evaluated the effects of ursolic acid, an active component isolated from herbal sources, on erlotinib‐resistant H1975 cells that harbour the L858R/T790M mutation. Experimental Approach Gene expression omnibus (GEO) profiles analyses was applied to detect differentially expressed genes in NSCLC cells harbouring 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 effects of ursolic acid 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 increased cell proliferation and motility in vitro. Silencing the CT45A2 expression strongly attenuated H1975 cells motility and growth. The anti‐cancer effect of ursolic acid was critically dependent on CT45A2 expression in H1975 cells. Ursolic acid suppressed CT45A2 gene transcription mediated by transcriptional factor TCF4 and β‐catenin signalling. Conclusions and Implications CT45A2 is a novel oncogene for NSCLC with an EGFR T790 mutation. Ursolic acid induced apoptosis and inhibited proliferation of H1975 cells by negatively regulating the β‐catenin/TCF4/CT45A2 signalling pathway. Therefore, ursolic acid may be a potential candidate treatment for NSCLC harbouring the EGFR‐L858R/T790M mutation.

Autophagy inhibition enhances the inhibitory�effects of ursolic acid on lung cancer cells

“…UA is a natural pentacyclic triterpenoid that possesses anticancer activities against a variety of cancers in vitro and in vivo (17,18,22,24,26). For example, UA has been shown to significantly suppress xenograft tumor growth in a human lung cancer H1975 xenograft mouse model (24). UA exhibits a low toxicity in human normal lung epithelial BEAS-2B cells, and exerts minimal toxic effects on the kidney and liver tissues in mice (24).…”

“…For example, UA has been shown to significantly suppress xenograft tumor growth in a human lung cancer H1975 xenograft mouse model (24). UA exhibits a low toxicity in human normal lung epithelial BEAS-2B cells, and exerts minimal toxic effects on the kidney and liver tissues in mice (24). Furthermore, UA has recently been promoted to enter clinical trials to investigate its effects on insulin sensitivity (phase II study) and muscle function in human sarcopenia (phase II and III studies) (52,53).…”

“…UA displays a wide range of pharmacological effects, such as anti-inflammatory (14,15), antioxidant (16), antitumor (17,18), cardioprotective (19) and immunomodulatory (20,21) activities. UA has been shown to possess a variety of anticancer capabilities in vitro and in vivo, including the ability to inhibit the proliferation of multiple types of tumor cells, induce apoptosis, induce cell cycle arrest, suppress tumor invasion, metastasis and angiogenesis (22)(23)(24)(25)(26)(27). However, the underlying anticancer mechanisms of UA in lung cancer are not yet fully understood.…”

Ursolic acid derivative UA232 evokes apoptosis of lung cancer cells induced by endoplasmic reticulum stress

“…Multiple studies further demonstrated that UA had more pharmacological effects, such as blocking the process of chronic disease (Yu et al 2017), radiosensitization (Yang et al 2015), neuroprotective (Habtemariam 2019), antidiabetic (Xu et al 2018), and antitumor (Zang et al 2014). Studies have confirmed that UA plays an antitumor role in a variety of tumours, including colorectal cancer (Kim et al 2018), breast cancer (Yin et al 2018), endometrial carcinoma (Achiwa et al 2013), and lung cancer (Yang et al 2019). UA plays an antitumor role in a variety of ways, including inhibition of proliferation, angiogenesis, invasion, metastasis, differentiation, and induction of tumour cell apoptosis (Zhang et al 2014).…”

“… 2013 ), and lung cancer (Yang et al. 2019 ). UA plays an antitumor role in a variety of ways, including inhibition of proliferation, angiogenesis, invasion, metastasis, differentiation, and induction of tumour cell apoptosis (Zhang et al.…”