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

Abstract

Abbreviations: NSCLC, non-small cell lung cancer; CDK, cyclin-dependent kinase; mTOR, mammalian target of rapamycin; p70S6K, ribosomal protein S6 kinase (70KD); CFSE, carboxyfluorescein diacetate succinimidyl ester; MK, midkine; miRNAs, microRNAsMicroRNas (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.

Targeting the Mammalian Target of Rapamycin in Lung Cancer

“…Diaporine inhibited tumor growth in H460 xenograft mice. 136 Additional natural compounds such as curcumin, resveratrol, ori-donin, quercetin, fisetin, indole-3-carbinol, isoflavones and polygonatum cyrtonema lectin do not inhibit mTOR directly, but effect expression or activity via mTOR pathway signaling modulation. 137,138 …”

Anti-fibrosis effect for Hirsutella sinensis mycelium based on inhibition of mTOR p70S6K phosphorylation

“…10 The mammalian target of rapamycin (mTOR) signaling pathway plays a core role in regulating cell proliferation, motility and survival. 11 Previous reports have shown that mTOR stimulation is associated with fibrotic diseases, including cardiac, liver and kidney fibrosis. Gui et al proved that mTOR activation in alveolar epithelial cells and autophagy in the pulmonary is associated with the development of PF.…”

The altered microRNA profile in andrographolide-induced inhibition of hepatoma tumor growth

“…3,6-dihydroxyflavone, diaporine A (Saini et al, 2011;Chang et al, 2012;Xia et al, 2012;Song et al, 2014). However, there is still no related report about the effects of Andro on miRNA expression profile when it exerts its inhibition on hepatoma tumor growth.…”