Rapid loss in the mitochondrial membrane potential during geranylgeranoic acid-induced apoptosis.

A synthetic geranylgeranoic acid (GGA) induced apoptotic cell death in a human hepatoma cell line, HuH-7, but not in mouse primary cultured hepatocytes. Prior to chromatin condensation, GGA induced a dramatic loss of the mitochondrial membrane potential in 1 hour and in a dose dependent manner in HuH-7 cells, but not in the primary hepatocytes. Pretreatment with synthetic tetrapeptide cysteine protease inhibitor, either acetyl-Tyr-Val-Ala-Asp-chloromethylketone or acetyl-Asp-Glu-Val-Asp-aldehyde, blocked GGA-induced apoptosis without preventing a rapid loss of the mitochondrial membrane potential. alpha-Tocopherol prevented the cells from GGA-induced apoptosis as well as from a rapid loss of the membrane potential. The present study strongly suggests that GGA induces apoptosis in hepatoma cells through derangement of mitochondrial function and subsequent activation of the cysteine protease cascade.