Fisetin (3,7,3',4'-tetrahydroxyflavone), a
flavonol compound of
flavonoids, exhibits a broad spectrum of biological activities including
anti-oxidant, anti-inflammatory, anti-
cancer and
neuroprotective effects. The aim of this study is to investigate the cytoprotective effect of
fisetin and the underlying molecular mechanism against
hypoxia-induced cell death in PC12 cells. The results of this study showed that
fisetin significantly restored the cell viability of PC12 cells under both
cobalt chloride (CoCl₂)- and low
oxygen-induced hypoxic conditions. Treatment with
fisetin successfully reduced the CoCl₂-mediated
reactive oxygen species (ROS) production, which was accompanied by an increase in the cell viability of PC12 cells. Furthermore, we found that treatment of PC12 cells with
fisetin markedly upregulated
hypoxia-inducible factor 1α (HIF-1α), its nuclear accumulation and the
hypoxia-response element (HRE)-driven transcriptional activation. The
fisetin-mediated cytoprotection during CoCl₂ exposure was significantly attenuated through the administration of HIF-1α
siRNA. Moreover, we demonstrated that
MAPK/ERK kinase 1/2 (MEK1/2),
p38 MAPK and
phosphatidylinositol 3-kinase (PI3 K) inhibitors significantly blocked the increase in cell survival that was induced by
fisetin treatment under hypoxic conditions. Consistently, increased phosphorylation of ERK, p38 and Akt
proteins was observed in PC12 cells treated with
fisetin. However, the
fisetin-induced HRE-driven transcription was not affected by inhibition of these
kinase signaling pathways. Current results reveal for the first time that
fisetin promotes cell survival and protects against
hypoxia-induced cell death through ROS scavenging and the activation of HIF1α-, MAPK/ERK-,
p38 MAPK- and PI3 K/Akt-dependent signaling pathways in PC12 cells.