6-dehydrogingerdione sensitizes human hepatoblastoma Hep G2 cells to TRAIL-induced apoptosis via reactive oxygen species-mediated increase of DR5.
The anticancer effects of 6-dehydrogingerdione (6-DG), a compound isolated from the rhizomes of Zingiber officinale , and its mechanisms of sensitization to TRAIL-induced apoptosis were studied using human hepatoblastoma Hep G2 cells. This study demonstrates for the first time that 6-DG-induced apoptosis might be executed via mitochondrial- and Fas receptor-mediated pathways. Further studies also demonstrated that 6-DG could sensitize Hep G2 cells to TRAIL-induced apoptosis. 6-DG also up-regulated Ser-15 phosphorylation and evoked p53 nuclear translocation. Abrogation of p53 expression by p53 small interfering RNA significantly attenuated 6-DG-induced DR5 expression, thus rendering these cells resistant to TRAIL-induced apoptosis. DR5 expression after 6-DG treatment was accompanied by provoking intracellular reactive oxygen species (ROS) generation. Pretreatment with N-acetyl-l-cysteine (NAC) attenuated 6-DG-induced DR5 expression and inhibited TRAIL-induced apoptosis. In contrast to Hep G2 cells, DR5 up-regulation and sensitization to TRAIL-induced apoptosis instigated by 6-DG were not observed in normal MDCK cells. Taken together, these data suggested that in addition to the mitochondrial- and Fas receptor-mediated apoptotic pathways involved, ROS-dependent and p53-regulated DR5 expression was also demonstrated to play a pivotal role in the synergistic enhancement of TRAIL-induced apoptosis instigated by 6-DG in Hep G2 cells.
Chen
Chung-Yi
CY
Department of Medical Technology, Fooyin University, Ta-Liao, Kaohsiung, Taiwan.
Tai
Cheng-Jeng
CJ
Cheng
Jiin-Tsuey
JT
Zheng
Juan-Juan
JJ
Chen
Ying-Zong
YZ
Liu
Tsan-Zon
TZ
Yiin
Shuenn-Jiun
SJ
Chern
Chi-Liang
CL
D000111:Acetylcysteine / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D006139:Guaiacol / Q000031:analogs & derivatives* / Q000494:pharmacology; D018197:Hepatoblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology*
D017382:Reactive Oxygen Species; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D006139:Guaiacol; C050872:gingerdione; D000111:Acetylcysteine