Zonal necrosis prevented by transduction of the artificial anti-death FNK protein.
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.
Asoh
S
S
Department of Biochemistry and Cell Biology, Institute of Development and Aging Sciences, Graduate School of Medicine, Nippon Medical School, Kawasaki-city, Kanagawa, Japan.
Mori
T
T
Nagai
S
S
Yamagata
K
K
Nishimaki
K
K
Miyato
Y
Y
Shidara
Y
Y
Ohta
S
S
D000255:Adenosine Triphosphate / Q000378:metabolism; D002251:Carbon Tetrachloride / Q000494:pharmacology; D061945:Caspase Inhibitors; D003907:Dexamethasone / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008928:Mitochondria / Q000378:metabolism; D009336:Necrosis / Q000139:chemically induced / Q000517:prevention & control*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D000097868:Polo-like Kinases
D000255:Adenosine Triphosphate; D002251:Carbon Tetrachloride; D061945:Caspase Inhibitors; D003907:Dexamethasone; D000431:Ethanol; D017346:Protein Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; C486256:PLK3 protein, human; D000097868:Polo-like Kinases