A novel small-molecule compound diaporine A inhibits non-small cell lung cancer growth by regulating miR-99a/mTOR signaling

Abstract

MicroRNAs (miRNAs) dysregulation is critically involved in lung cancer. Regulating miRNAs by natural agents may be a new strategy for cancer treatment. We previously found that a novel small-molecule compound diaporine A (D261), a natural product of endophytic fungus 3lp-10, had potential anti-cancer activites. In the present study, the inhibitory effect of D261 on non-small cell lung cancer (NSCLC) growth and its possible mechanisms involving miRNA regulation were investigated. By cell viability assay, cell proliferation analysis, and clonal growth assay, we proved that D261 effectively inhibited the proliferation of NSCLC cells (NCI-H460 and A549) in vitro. Administration of D261 (5 mg/kg) to NCI-H460 xenografts bearing mice also inhibited tumor growth and decreased the expression of cell proliferation regulator, midkine. Moreover, D261 induced cell cycle arrest with a reduced expression of various G₁/S transition-related molecules including cyclin D1, cyclin E1, CDK4, and CDK2, but without influencing apoptosis in NSCLC cells. Intriguingly, D261 modified expressions of some miRNAs and especially upregulated miR-99a, whose direct target was mammalian target of rapamycin (mTOR). Furthermore, overexpression of miR-99a antagonized the anti-tumor actions of D261 including the suppression of mTOR pathway activation, cell cycle-related proteins and cell growth. In addition, blocking of miR-99a expression by transfection of miR-99a inhibitors before D261 treatment counteracted the anti-tumor effects of D261. These data suggest that miR-99a/mTOR pathway was involved in D261-induced tumor suppression in NSCLC cells. D261 might be a potent anti-cancer agent by upregulating miR-99a expression.

Keywords: :

• diaporine A
• natural agent
• NSCLC
• cell cycle
• G1/S transition
• miR-99a
• mTOR

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

This work was supported by the Natural Science Foundation for Young Scholars of Jiangsu Province (BK20140615), the National Natural Science Foundation of China (81121062), the Medical Science and Technology Development Foundation of Nanjing (201308002, JQX13004, YKK12076, and QRX11243), the Scientific Research Foundation of Graduate School of Nanjing University (2012CL03), and the Nature Science Foundation of Colleges and Universities of Jiangsu Province (12KJD180004).