title: 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 G 1/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.
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology; Division of Immunology; Medical School; Nanjing University; Nanjing, PR China.
authors.forename: Yuxian
authors.initials: Y
authors.lastname: Song
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology; Division of Immunology; Medical School; Nanjing University; Nanjing, PR China.
authors.forename: Huan
authors.initials: H
authors.lastname: Dou
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology; Division of Immunology; Medical School; Nanjing University; Nanjing, PR China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Central Laboratory of Nanjing First Hospital; Nanjing Medical University; Nanjing, PR China.
authors.forename: Shuli
authors.initials: S
authors.lastname: Zhao
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology; Division of Immunology; Medical School; Nanjing University; Nanjing, PR China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Wang
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology; Division of Immunology; Medical School; Nanjing University; Nanjing, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Gong
authors.affiliation: Nanjing Xiaozhuang College; Nanjing, PR China.
authors.forename: Junli
authors.initials: J
authors.lastname: Zhao
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology; Division of Immunology; Medical School; Nanjing University; Nanjing, PR China.
authors.forename: Erguang
authors.initials: E
authors.lastname: Li
authors.affiliation: Institute of Functional Biomolecules; State Key Laboratory of Pharmaceutical Biotechnology; School of Lifesciences; Nanjing University; Nanjing, PR China.
authors.forename: Renxiang
authors.initials: R
authors.lastname: Tan
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology; Division of Immunology; Medical School; Nanjing University; Nanjing, PR China; Jiangsu Key Laboratory of Molecular Medicine; Nanjing, PR China.
authors.forename: Yayi
authors.initials: Y
authors.lastname: Hou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004852:Epoxy Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005658:Fungi; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology / Q000627:therapeutic use*; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D000078792:Midkine; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D016213:Cyclins; D016207:Cytokines; D004852:Epoxy Compounds; D006576:Heterocyclic Compounds, 4 or More Rings; C561679:MIRN99 microRNA, human; D035683:MicroRNAs; C000596497:diaporine A; D000078792:Midkine; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D018844:Cyclin-Dependent Kinases
keywords: G1/S transition; NSCLC; cell cycle; diaporine A; mTOR; miR-99a; natural agent