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KMID : 0578320130350010032
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Molecules and Cells
2013 Volume.35 No. 1 p.32 ~ p.40
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Sub-Toxic Dose of Apigenin Sensitizes HepG2 Cells to TRAIL through ERK-Dependent Up-Regulation of TRAIL Receptor DR5
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Kim Eun-Young
Yu Ji-Sun
Yang Mi-Hi
Kim An-Keun
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Abstract
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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is regarded as a promising candidate for anticancer
therapy due to its selective toxicity to cancer cells. Nevertheless, because of TRAIL resistance in some cancer
cells, combined treatment with sensitizing agents is required to enhance the anticancer potential of TRAIL. In this
study, we investigated the underlying mechanism of apigenin-induced sensitization of HepG2 cells to TRAIL-induced
cell death. Synergistic induction of apoptosis by combination was confirmed by examining the typical morphology
changes of apoptosis, PARP-cleavage, and activation of effector caspases. Z-VAD-fmk, a pan-caspase
inhibitor, inhibited the enhanced cell death by combined treatment of apigenin and TRAIL, demonstrating that a
caspase-dependent pathway is involved in apigenin/TRAILmediated apoptosis. In addition, we found that apigenin/
TRAIL co-treatment up-regulates DR5 cell surface expression. The synergistic induction of cell death by the apigenin/
TRAIL combination was significantly attenuated by DR5 blocking chimera antibody. Next, using pharmacological
inhibitors, we found that ERK activation is involved in the induction of DR5 expression. Inhibition of ERK1/2 by
U0126 significantly decreased the apigenin/TRAIL-induced DR5 expression and apoptosis. Taken together, our results
indicate that apigenin can enhance the apoptotic effect of TRAIL via ERK-induced up-regulation of DR5.
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KEYWORD
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apigenin, apoptosis, DR5, ERK, HepG2, TRAIL
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