title: Cytoprotective effects of fisetin against hypoxia-induced cell death in PC12 cells.
abstract: 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.
authors.affiliation: Center of Medical Genetics, Buddhist Tzu Chi General Hospital, Hualien 970, Taiwan. pyc571@gmail.com.
authors.forename: Pei-Yi
authors.initials: PY
authors.lastname: Chen
authors.forename: Yi-Ru
authors.initials: YR
authors.lastname: Ho
authors.forename: Ming-Jiuan
authors.initials: MJ
authors.lastname: Wu
authors.forename: Shun-Ping
authors.initials: SP
authors.lastname: Huang
authors.forename: Po-Kong
authors.initials: PK
authors.lastname: Chen
authors.forename: Mi-Hsueh
authors.initials: MH
authors.lastname: Tai
authors.forename: Chi-Tang
authors.initials: CT
authors.lastname: Ho
authors.forename: Jui-Hung
authors.initials: JH
authors.lastname: Yen
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003035:Cobalt / Q000633:toxicity; D005419:Flavonoids / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D044948:Flavonols; D016166:Free Radical Scavengers / Q000737:chemistry / Q000494:pharmacology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D016716:PC12 Cells; D064209:Phytochemicals / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D034622:RNA Interference; D051381:Rats; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020218:Response Elements / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D005419:Flavonoids; D044948:Flavonols; D016166:Free Radical Scavengers; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018696:Neuroprotective Agents; D064209:Phytochemicals; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D003035:Cobalt; C018021:cobaltous chloride; C017875:fisetin