TRAIL induces apoptosis in a variety of
tumor cells. However, development of resistance to TRAIL is a major obstacle to more effective
cancer treatment. Therefore, novel pharmacological agents that enhance sensitivity to TRAIL are necessary. In the present study, we investigated the molecular mechanisms by which
ilimaquinone isolated from a sea sponge sensitizes human
colon cancer cells to TRAIL.
Ilimaquinone pretreatment significantly enhanced TRAIL-induced apoptosis in HCT 116 cells and sensitized
colon cancer cells to TRAIL-induced apoptosis through increased
caspase-8, -3 activation, PARP cleavage, and DNA damage.
Ilimaquinone also reduced the cell survival
proteins Bcl2 and Bcl-xL, while strongly up-regulating
death receptor (DR) 4 and DR5 expression. Induction of DR4 and DR5 by
ilimaquinone was mediated through up-regulation of
CCAAT/enhancer-binding protein homologous
protein (CHOP). The up-regulation of CHOP, DR4 and DR5 expression was mediated through activation of
extracellular-signal regulated kinase (ERK) and
p38 mitogen-activated protein kinase (MAPK) signaling pathways. Finally, the generation of ROS was required for CHOP and DR5 up-regulation by
ilimaquinone. These results demonstrate that
ilimaquinone enhanced the sensitivity of human
colon cancer cells to TRAIL-induced apoptosis through ROS-ERK/
p38 MAPK-CHOP-mediated up-regulation of DR4 and DR5 expression, suggesting that
ilimaquinone could be developed into an adjuvant chemotherapeutic
drug.