Luteolin induces microRNA-132 expression and modulates neurite outgrowth in PC12 cells

PLoS One. 2012;7(8):e43304. doi: 10.1371/journal.pone.0043304. Epub 2012 Aug 16.

Abstract

Luteolin (3',4',5,7-tetrahydroxyflavone), a food-derived flavonoid, has been reported to exert neurotrophic properties that are associated with its capacity to promote neuronal survival and neurite outgrowth. In this study, we report for the first time that luteolin induces the persistent expression of microRNA-132 (miR-132) in PC12 cells. The correlation between miR-132 knockdown and a decrease in luteolin-mediated neurite outgrowth may indicate a mechanistic link by which miR-132 functions as a mediator for neuritogenesis. Furthermore, we find that luteolin led to the phosphorylation and activation of cAMP response element binding protein (CREB), which is associated with the up-regulation of miR-132 and neurite outgrowth. Moreover, luteolin-induced CREB activation, miR-132 expression and neurite outgrowth were inhibited by adenylate cyclase, protein kinase A (PKA) and MAPK/ERK kinase 1/2 (MEK1/2) inhibitors but not by protein kinase C (PKC) or calcium/calmodulin-dependent protein kinase II (CaMK II) inhibitors. Consistently, we find that luteolin treatment increases ERK phosphorylation and PKA activity in PC12 cells. These results show that luteolin induces the up-regulation of miR-132, which serves as an important regulator for neurotrophic actions, mainly acting through the activation of cAMP/PKA- and ERK-dependent CREB signaling pathways in PC12 cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Enzyme Inhibitors / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Luteolin / pharmacology*
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Neurites / drug effects*
  • Phosphorylation / drug effects
  • Rats
  • Signal Transduction / drug effects

Substances

  • Cyclic AMP Response Element-Binding Protein
  • Enzyme Inhibitors
  • MIRN132 microRNA, rat
  • MicroRNAs
  • Extracellular Signal-Regulated MAP Kinases
  • Luteolin

Grant support

This study was supported by grant NSC-97-2320-B-320-011-MY3 and NSC-99-2320-B-041-005 -MY3 from National Science Council, Taiwan, ROC; and by grant TCMRC-P-100006 from Tzu Chi University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.