Luteolin modulates 6-hydroxydopamine-induced transcriptional changes of stress response pathways in PC12 cells.
The neurotoxin 6-hydroxydopamine (6-OHDA), which causes transcriptional changes associated with oxidative and proteotoxic stress, has been widely used to generate an experimental model of Parkinson's disease. The food-derived compound luteolin has multi-target actions including antioxidant, anti-inflammatory and neurotrophic activities. The aim of this study is to investigate how luteolin affects 6-OHDA-mediated stress response pathways. The results showed that when PC12 cells were pre-treated with luteolin (20 µM) 30 min prior to 6-OHDA (100 µM) exposure, 6-OHDA-induced ROS overproduction, cytotoxicity, caspase-3 activation, and mRNA expression of BIM, TRB3 and GADD34 were significantly attenuated. Moreover, 6-OHDA-mediated cell cycle arrest and transcription of p53 target genes, p21, GADD45α and PUMA, were reduced by luteolin. Luteolin also significantly down-regulated 6-OHDA-mediated unfolded protein response (UPR), leading to decreases in phospho-eIF2α, ATF4, GRP78 and CHOP. In addition, luteolin attenuated 6-OHDA-induced Nrf2-mediated HO-1 and GCLC. Taken together, these results suggest that diminishing intracellular ROS formation and down-regulation of p53, UPR and Nrf2-ARE pathways may be involved in the neuroprotective effect of luteolin.
Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan, Taiwan.
Ling-Wei
LW
Hu
Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, Taiwan.
Jui-Hung
JH
Yen
Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan, Taiwan.
Yi-Ting
YT
Shen
Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan, Taiwan.
Kuan-Yi
KY
Wu
Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan, Taiwan.
Ming-Jiuan
MJ
Wu
D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D005786:Gene Expression Regulation / Q000187:drug effects*; D006360:Heat-Shock Proteins / Q000235:genetics; D047311:Luteolin / Q000494:pharmacology*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D016627:Oxidopamine / Q000494:pharmacology*; D016716:PC12 Cells; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects* / Q000235:genetics*; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D015533:Transcriptional Activation / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D051702:Activating Transcription Factor 6; D000091342:Endoplasmic Reticulum Chaperone BiP; C051684:GRP78 protein, rat; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D051267:NF-E2-Related Factor 2; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; D016627:Oxidopamine; D047311:Luteolin