Exp Mol Med.  2008 Apr;40(2):186-195. 10.3858/emm.2008.40.2.186.

Prevention of TNF-induced necrotic cell death by rottlerin through a Nox1 NADPH oxidase

Affiliations
  • 1Department of Pharmacology, Research Institute for Medical Science, Infection Signaling Network Research Center, College of Medicine, Chungnam National University, Daejeon 301-131, Korea. gmhur@cnu.ac.kr
  • 2Department of Pathology, Research Institute for Medical Science, Infection Signaling Network Research Center, College of Medicine, Chungnam National University, Daejeon 301-131, Korea.
  • 3Department of Biochemistry, Research Institute for Medical Science, Infection Signaling Network Research Center, College of Medicine, Chungnam National University, Daejeon 301-131, Korea.
  • 4Department of Physiology, College of Medicine, Inje University, Busan 614-735, Korea.

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.

Keyword

cell death; necrosis; NADPH oxidase 1; rottlerin; superoxidase; tumor necrosis factor-alpha
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