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

Abstract

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 absence or presence of GGOH. Activation of caspase‐8/‐9/‐3 in HuH‐7 cells was found after 8 h treatment with GGOH, at which tune DNA fragmentation and loss of mitochondrial transmembrane potential (ΔΨm) occurred. HuH‐7 cells do not express Bcl‐2; however, down‐regulation of Bcl‐xL expression preceded activation of the caspase cascade in GGOH‐treated HuH‐7 cells, while Bax expression was not changed by GGOH treatment. Addition of caspase inhibitors restored the decreased cell viability of HuH‐7 cells by GGOH, including ΔΨm, to the baseline level, which indicated that caspase triggers mitochondria‐dependent apoptotic pathways in GGOH‐treated HuH‐7 cells. Similarly, GGOH‐mediated apoptosis of HuH‐7 cells was clearly prevented by coadministration of ursodeoxycholic acid (UDCA), which led to restoration of the level of Bcl‐xL expression. Activation of caspase‐8/‐9/‐3, as well as ΔΨm, by GGOH treatment was suppressed by addition of UDCA. Our results 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.