Geranylgeraniol, an intermediate product in mevalonate pathway, induces apoptotic cell death in human hepatoma cells: Death receptor-independent activation of caspase-8 with down-regulation of Bcl-xL expression

Geranylgeraniol (GGOH), an intermediate of mevalonate metabolism, is known to induce apoptosis in various lines of cancer cells. The present study was undertaken to clarify the signaling pathways of apoptosis induced by GGOH in human hepatoma cells. HuH-7 human hepatoma cells were incubated in the a bsence or presence of GGOH. Activation of caspase-8/-9/-3 in HuH-7 cells wa s found after 8 h treatment with GGOH, at which time DNA fragmentation and loss of mitochondrial transmembrane potential (Delta Psim) occurred. HuH-7 cells do not express Bcl-2; however, downregulation of Bcl-xL expression pr eceded activation of the caspase cascade in GGOH-treated HuH-7 cells, while Bax expression was not changed by GGOH treatment. Addition of caspase inhi bitors restored the decreased cell viability of HuH-7 cells by GGOH, includ ing Delta Psim, to the baseline level, which indicated that caspase trigger s mitochondria-dependent apoptotic pathways in GGOH-treated HuH-7 cells. Si milarly, GGOH-mediated apoptosis of HuH-7 cells was clearly prevented by co administration of ursodeoxycholic acid (UDCA), which led to restoration of the level of Bcl-xL expression. Activation of caspase-8/-9/-3, as well as D elta Psim, by GGOH treatment was suppressed by addition of UDCA. Our result s indicate that activation of the caspase cascade initiating from caspase-8 , which could be accelerated by down-regulation of Bcl-xL expression, plays a key role in an apoptotic process induced by GGOH in human hepatoma cells .