Prevention of TNF-induced necrotic cell death by rottlerin through a Nox1 NADPH oxidase.
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.
Byun
Hee Sun
HS
Department of Pharmacology, Research Institute for Medical Science, Infection Signaling Network Research Center, College of Medicine, Chungnam National University, Daejeon 301-131, Korea.
Won
Minho
M
Park
Kyeong Ah
KA
Kim
Young-Rae
YR
Choi
Byung Lyul
BL
Lee
Hyunji
H
Hong
Jang Hee
JH
Piao
Longzhen
L
Park
Jongsun
J
Kim
Jin Man
JM
Kweon
Gi Ryang
GR
Kang
Sung Hyun
SH
Han
Jin
J
Hur
Gang Min
GM
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
D000098:Acetophenones; D001578:Benzopyrans; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; C085746:rottlerin