Overcoming cisplatin resistance of human lung cancer by sinomenine through targeting the miR-200a-3p-GLS axis

Abstract

Lung cancer, a malignant disease, is one of the leading causes of patient death. Non‐small cell lung cancer (NSCLC) is the most common type of lung cancer. Currently, chemotherapeutic agents such as cisplatin are widely used against lung cancer. However, development of chemoresistance, which led to poor prognosis and low survival rate greatly limited the clinical applications of cisplatin. Sinomenine (SIN) is a bioactive component of sinomenium acutum. Accumulating evidence revealed SIN exhibits potential anti-tumor activities in various types of cancers. However, the precise molecular mechanisms for the sinomenine-induced anti-cancer effects have not been fully elucidated. Here, we assessed the effects of sinomenine on cisplatin sensitivity in NSCLC cells. The combination of SIN with cisplatin showed synergistically inhibitory effects on lung cancer cells by calculating the combination index (CI value) using the Calcusyn 2.0 software. Moreover, we detected that the glutamine metabolism was significantly suppressed by sinomenine treatments in lung cancer cells. Under low glutamine supply, A549 cells showed less sensitivity to sinomenine treatments. Meanwhile, miR-200a-3p was found to be significantly induced by SIN treatments. We demonstrated a suppressive role of miR-200a-3p on glutamine metabolism. Furthermore, miR-200a-3p was downregulated but the glutamine metabolism was significantly hyperactive in A549 cisplatin resistant cells compared with parental cells. Bioinformatical analysis and luciferase assay demonstrated the glutaminase (GLS), a key enzyme of glutamine metabolism, is the direct target of miR-200a-3p in lung cancer cells. Finally, rescue experiments demonstrated that recovery of GLS in miR-200a-3p overexpressing-cisplatin resistant cells successfully overrode the sinomenine-mediated cisplatin sensitization. In summary, this study revealed a new molecular mechanism for the sinomenine-promoted cisplatin sensitization, contributing to investigating the sinomenine-based therapeutic agents against chemoresistant NSCLC.