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KMID : 0620920080400020186
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Experimental & Molecular Medicine
2008 Volume.40 No. 2 p.186 ~ p.195
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Prevention of TNF-induced necrotic cell death by rottlerin through a Nox1 NADPH oxidase
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Byun Hee-Sun
Kim Jin-Man
Han Jin
Won Min-Ho
Park Jong-Sun
Hur Gang-Min
Hong Jang-Hee
Kang Sung-hyun
Park Kyeong-Ah
Kim Young-Rae
Choi Byung-Lyul
Lee Hyun-Ji
Piao Longzhen
Kweon Gi-Ryang
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Abstract
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Previous studies have demonstrated that rottlerin, a specific PKCδ inhibitor, potentiates death receptormediated 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-δ. 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.
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KEYWORD
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cell death, necrosis, NADPH oxidase 1, rottlerin, superoxidase, tumor necrosis factor-α
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