Guggulsterone sensitizes hepatoma cells to TRAIL-induced apotosis through the induction of CHOP-dependent DR5: involvement of ROS-dependent ER-stress = guggulsterone의 간암세포에서 TRAIL유도 아포토시스의 촉진

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Title
Guggulsterone sensitizes hepatoma cells to TRAIL-induced apotosis through the induction of CHOP-dependent DR5: involvement of ROS-dependent ER-stress = guggulsterone의 간암세포에서 TRAIL유도 아포토시스의 촉진
Author(s)
D O Moon; S Y Park; Y H Choi; Jong Seog Ahn; G Y Kim
Bibliographic Citation
Biochemical Pharmacology, vol. 82, no. 11, pp. 1641-1650
Publication Year
2011
Abstract
Guggulsterone (GGS) has anti-tumor and anti-angiogenesis potential by suppressing nuclear factor-κB and STAT3 activity. Although GGS has been suggested as a potential therapeutic agent for treating various cancers, the underlying molecular mechanisms are unknown. Therefore, we investigated whether GGS sensitizes hepatocellular carcinoma cells (HCC) to apoptosis mediated by tumor necrosis factor-related apoptosis inducing ligand (TRAIL). The apoptotic mechanism induced by treatment with a GGS/TRAIL combination involved the loss of mitochondrial transmembrane potential and consequent activation of caspases. GGS also induced upregulation of the death receptor DR5 for TRAIL. The effects seemed to be associated with eIF2α and CHOP activation, which are related to the endoplasmic reticulum (ER) stress response and apoptosis. This relationship was suggested by the observation that CHOP downregulation by specific siRNA attenuated both GGS-mediated DR5 upregulation and the cytotoxicity induced by GGS/TRAIL co-treatment. Moreover, salubrinal, a specific eIF-2α phosphorylation-inducing agent, enhanced the expression of CHOP and DR5 induced by GGS and sensitized cells to GGS/TRAIL-induced apoptosis. Thus, GGS-induced eIF2α phosphorylation seems to be important for CHOP and DR5 upregulation. Furthermore, these events were accompanied by an increase in the generation of reactive oxygen species. Pretreatment with N-acetyl-l-cysteine and glutathione inhibited GGS-induced ER-stress, and CHOP and DR5 upregulation and almost completely blocked GGS/TRAIL-induced apoptosis. These results collectively indicate that DR5 induction via eIF-2α and CHOP is crucial for the marked synergistic effects induced by TRAIL and GGS. Taken together, these results indicate that a GGS/TRAIL combination could represent a novel important tool for cancer therapy.
Keyword
CHOPER stressGuggulsteroneTRAIL
ISSN
0006-2952
Publisher
Elsevier
DOI
http://dx.doi.org/10.1016/j.bcp.2011.08.019
Type
Article
Appears in Collections:
Ochang Branch Institute > Chemical Biology Research Center > 1. Journal Articles
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