Zonal necrosis prevented by transduction of the artificial anti-death FNK protein

• Published in: Cell death and differentiation Vol. 12; no. 4; pp. 384 - 394
• Main Authors: Asoh, S, Mori, T, Nagai, S, Yamagata, K, Nishimaki, K, Miyato, Y, Shidara, Y, Ohta, S
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01-04-2005
• Subjects: Adenosine Triphosphate - metabolism; Apoptosis; Biochemistry; Carbon; Carbon Tetrachloride - pharmacology; Caspase Inhibitors; Cell death; Dexamethasone - pharmacology; Endoplasmic reticulum; Ethanol - pharmacology; Humans; Ischemia; Liver; Liver - metabolism; Liver - pathology; Mitochondria - metabolism; Necrosis - chemically induced; Necrosis - prevention & control; Oxidative stress; Protein-Serine-Threonine Kinases - metabolism; Proteins; Tumor Necrosis Factor-alpha - metabolism; Japan
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/sj.cdd.4401569

Protection of cells from necrosis would be important for many medical applications. Here, we show protein transduction domain (PTD)-FNK therapeutics based on protein transduction to prevent necrosis and acute hepatic injury with zonal death induced by carbon tetrachloride (CCl4). PTD-FNK is a fusion protein comprising the HIV/Tat PTD and FNK, a gain-of-function mutant of anti-apoptotic Bcl-x(L). PTD-FNK protected hepatoma HepG2 from necrotic death induced by CCl4, and additionally, increased the apoptotic population among cells treated with CCl4. A concomitant treatment with a pan-caspase inhibitor Z-VAD-FMK (N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone), which alone could not prevent the necrosis, protected these cells from the apoptosis. When pre-injected intraperitoneally, PTD-FNK markedly reduced zonal liver necrosis caused by CCl4. Moreover, injection of PTD-FNK accompanied by Z-VAD-FMK suppressed necrotic injury even after CCl4 administration. These results suggest that PTD-FNK has great potential for clinical applications to prevent cell death, whether from apoptosis or necrosis, and organ failure.