title: Prevention of TNF-induced necrotic cell death by rottlerin through a Nox1 NADPH oxidase.
abstract: Previous studies have demonstrated that rottlerin, a specific PKCdelta inhibitor, potentiates death receptor- mediated apoptosis through a cytochrome c-dependent or -independent pathway. However, its ability to regulate necrotic cell death, as well as the underlying mechanism, remains unknown. We found that in murine fibrosarcoma L929 cells, treatment with rottlerin protected the cells against TNF-induced necrosis, whereas it sensitized the cells to apoptosis induced by co-treatment with Hsp90 inhibitor geldanamycin and TNF, in a manner independent of its ability to inhibit PKC-delta. TNF treatment induced rapid accumulation of mitochondrial superoxide (O2-) through the Nox1 NADPH oxidase when cells undergo necrosis. Moreover, pretreatment with rottlerin failed to induce the GTP-bound form of small GTPase Rac1 by TNF treatment, and subsequently suppressed mitochondrial O2- production and poly(ADP-ribose) polymerase activation, thus inhibiting necrotic cell death. Therefore, our study suggests that Nox1 NADPH oxidase is a new molecular target for anti-necrotic activity of rottlerin upon death-receptor ligation.
authors.affiliation: Department of Pharmacology, Research Institute for Medical Science, Infection Signaling Network Research Center, College of Medicine, Chungnam National University, Daejeon 301-131, Korea.
authors.forename: Hee Sun
authors.initials: HS
authors.lastname: Byun
authors.forename: Minho
authors.initials: M
authors.lastname: Won
authors.forename: Kyeong Ah
authors.initials: KA
authors.lastname: Park
authors.forename: Young-Rae
authors.initials: YR
authors.lastname: Kim
authors.forename: Byung Lyul
authors.initials: BL
authors.lastname: Choi
authors.forename: Hyunji
authors.initials: H
authors.lastname: Lee
authors.forename: Jang Hee
authors.initials: JH
authors.lastname: Hong
authors.forename: Longzhen
authors.initials: L
authors.lastname: Piao
authors.forename: Jongsun
authors.initials: J
authors.lastname: Park
authors.forename: Jin Man
authors.initials: JM
authors.lastname: Kim
authors.forename: Gi Ryang
authors.initials: GR
authors.lastname: Kweon
authors.forename: Sung Hyun
authors.initials: SH
authors.lastname: Kang
authors.forename: Jin
authors.initials: J
authors.lastname: Han
authors.forename: Gang Min
authors.initials: GM
authors.lastname: Hur
mesh_terms: D000098:Acetophenones / Q000494:pharmacology*; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000494:pharmacology
chemical_list: D000098:Acetophenones; D001578:Benzopyrans; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; C085746:rottlerin