Induction of adaptive response and enhancement of PC12 cell tolerance by 7-hydroxycholesterol and 15-deoxy-delta(12,14)-prostaglandin J2 through up-regulation of cellular glutathione via different mechanisms.
Increasing evidence suggests an adaptive response induced by reactive oxygen species and other physiologically existing oxidative stimuli. We have recently reported that a variety of lipid peroxidation products at sublethal concentrations could induce adaptive response and enhance PC12 cell tolerance, although the detailed underlying molecular mechanisms have not been clearly clarified. In the present study, we found that both 7-hydroxycholesterol (7-OHCh) and 15-deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2) at sublethal concentrations significantly increased the cellular GSH as well as the enzyme activity of glutamate-cysteine ligase (GCL), the rate-limiting enzyme of GSH synthesis. Depletion of cellular GSH by buthionine sulfoximine completely abolished the adaptive response. Interestingly, treatment with 15d-PGJ2 significantly increased the gene expression of both subunits of GCL in an NF-E2-related factor 2 (Nrf2)-dependent manner, whereas neither 7-OHCh induced any considerable changes on the GCL gene expression nor did the Nrf2-small interfering RNA treatment exert any appreciable effects on the GSH elevation and subsequent adaptive response induced by 7-OHCh. These results demonstrate that the adaptive response induced by both 7-OHCh and 15d-PGJ2 is mediated similarly through the up-regulation of GSH but via different mechanisms.
Human Stress Signal Research Center, National Institute of Advanced Industrial Science and Technology, 1-8-31, Midorigaoka, Ikeda, Osaka, 563-8577, Japan. zhihua-chen@aist.go.jp
Zhi-Hua
ZH
Chen
Yasukazu
Y
Yoshida
Yoshiro
Y
Saito
Azusa
A
Sekine
Noriko
N
Noguchi
Etsuo
E
Niki
D000818:Animals; D015153:Blotting, Western; D002470:Cell Survival; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000378:metabolism*; D006888:Hydroxycholesterols / Q000494:pharmacology*; D016716:PC12 Cells; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D015854:Up-Regulation
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D006888:Hydroxycholesterols; D034741:RNA, Small Interfering; C011724:cholest-5-en-3 beta,7 alpha-diol; D005978:Glutathione; D015230:Prostaglandin D2