A novel small-molecule compound diaporine A inhibits non-small cell lung cancer growth by regulating miR-99a/mTOR signaling
A novel small-molecule compound diaporine A inhibits non-small cell lung cancer growth by regulating miR-99a/mTOR signaling
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DOI：
10.4161/cbt.29925
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发表时间：
2014-01-01
影响因子：
3.6
通讯作者：
Hou, Yayi
中科院分区：
文献类型：
--
作者：
Song, Yuxian;Dou, Huan;Hou, Yayi
MicroRNAs （miRNAs）失调在肺癌中起着至关重要的作用。通过天然药物调节mirna可能是癌症治疗的新策略。我们之前发现内生真菌3lp-10的天然产物一种新的小分子化合物地波碱a （D261）具有潜在的抗癌活性。本研究探讨了D261对非小细胞肺癌（NSCLC）生长的抑制作用及其可能涉及miRNA调控的机制。通过细胞活力实验、细胞增殖实验和克隆生长实验，证明D261能有效抑制NSCLC细胞（NCI-H460和A549）的体外增殖。D261 （5 mg/kg）对携带NCI-H460异种移植物的小鼠也能抑制肿瘤生长，降低细胞增殖调节因子midkine的表达。此外，D261诱导细胞周期阻滞，减少各种G(1)/S过渡相关分子（包括cyclin D1、cyclin E1、CDK4和CDK2）的表达，但不影响NSCLC细胞的凋亡。有趣的是，D261修饰了一些mirna的表达，特别是上调了miR-99a，其直接靶点是哺乳动物雷帕霉素靶点（mTOR）。此外，过表达miR-99a可拮抗D261的抗肿瘤作用，包括抑制mTOR通路激活、细胞周期相关蛋白和细胞生长。此外，在D261治疗前通过转染miR-99a抑制剂阻断miR-99a表达会抵消D261的抗肿瘤作用。这些数据表明，miR-99a/mTOR通路参与了d261诱导的NSCLC细胞肿瘤抑制。D261可能通过上调miR-99a的表达而成为一种有效的抗癌药物。
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.