Abstract
Lung cancer is a leading cause of cancer-related deaths worldwide. NOTCH3 signaling is mainly expressed in non-small cell lung carcinoma (NSCLC), and has been proposed as a therapeutic target of NSCLC. While, few agents for preventing or treating NSCLC via targeting NOTCH3 signaling are used in modern clinical practice. Evodiamine (EVO), an alkaloid derived from Euodiae Fructus, possesses low toxicity and has long been shown to exert anti-lung cancer activity. However, the underlying anti-lung cancer mechanisms of EVO are not yet fully understood. In this study, we explored the involvement of NOTCH3 signaling in the anti-lung cancer effects of EVO. Urethane-induced lung cancer mouse model and two NSCLC cell models, A549 and H1299, were used to evaluate the in vivo and in vitro anti-lung cancer action of EVO. A DNA methyltransferase inhibitor was employed to investigate the role of NOTCH3 signaling in the anti-lung cancer effects of EVO. Results showed that EVO potently reduced tumor size and tumor numbers in mice, and inhibited NOTCH3 in the tumors. EVO also dramatically reduced cell viability, induced G2/M cell cycle arrest, inhibited cell migration and reduced stemness in cultured NSCLC cells. Mechanistic studies showed that EVO potently inhibited NOTCH3 signaling by activation of DNMTs-induced NOTCH3 methylation. Importantly, inhibition of NOTCH3 methylation in NSCLC cells diminished EVO’s anti-NSCLC effects. Collectively, EVO, a novel NOTCH3 methylation stimulator, exerted potent anti-lung cancer effects partially by inhibiting NOTCH3 signaling. These findings provide new insight into the EVO’s anti-NSCLC action, and suggest a potential role of EVO in lung cancer prevention and treatment.
Highlights
Lung cancer is one of the most prevalent cancer types worldwide, with approximately 1.8 million newly diagnosed cases every year (Torre et al, 2015)
Propidium iodide (PI) staining, CD44 and CD133 were purchased from Biosciences (BD Biosciences, NJ, United States). β-actin, E-cadherin, N-cadherin and Vimentin primary antibodies were purchased from Santa Cruz Biotechnology (Santa Cruz, CA, United States). cdc2, cyclinB1, DNMT1, DNMT3A, DNMT3B, Histone H3 primary antibodies and HRP-conjugated secondary antibody were obtained from Cell Signaling Technology Inc. (Beverly, MA, United States)
We demonstrate that a novel NOTCH3 methylation stimulator EVO exerts anti-lung cancer activities and inhibits NOTCH3 signaling
Summary
Lung cancer is one of the most prevalent cancer types worldwide, with approximately 1.8 million newly diagnosed cases every year (Torre et al, 2015). It is generally consisting of two subtypes: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) (Zou et al, 2015). Most of the chemotherapeutics have failed in NSCLC treatment due to their limitations, e.g., drug resistance, high toxicities, and so on (Alberg et al, 2013; Tong et al, 2016). Molecule targeted therapy has achieved great progress in NSCLC because of the better understanding of the mechanisms of tumorigenesis and signal transduction pathway as well as the metabolic process in lung cancer. Almost all of the patients would face drug resistance finding new therapeutic targets become the research focus
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