Abstract
Luteolin, a naturally occurring flavonoid, induces apoptosis in various cancer cells. Little is known however concerning the underlying molecular mechanisms responsible for this activity. In this report, we reveal a novel mechanism by which luteolin-induced apoptosis occurs, and show for the first time that the apoptosis by luteolin is mediated through death receptor 5 (DR5) upregulation. Luteolin markedly induced the expression of DR5, along with Bcl-2-interacting domain cleavage and the activation of caspase-8, -10, -9 and -3. In addition, suppression of DR5 expression with siRNA efficiently reduced luteolin-induced caspase activation and apoptosis. Human recombinant DR5/Fc also inhibited luteolin-induced apoptosis. On the other hand, luteolin induced neither DR5 protein expression nor apoptosis in normal human peripheral blood mononuclear cells. These results suggest that DR5 induced by luteolin plays a role in luteolin-induced apoptosis, and raises the possibility that treatment with luteolin might be promising as a new therapy against cancer.
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Abbreviations
- DR5:
-
death receptor 5
- TNF:
-
tumor necrosis factor
- TNF-R:
-
tumor necrosis factor-receptor
- TRAIL:
-
tumor necrosis factor-related apoptosis-inducing ligand
- Bid:
-
Bcl-2-interacting domain
- PBMC:
-
peripheral blood mononuclear cells
- GAPDH:
-
glycelaldehyde-3-phosphate dehydrogenase
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Acknowledgements
We thank Dr Takafumi Kimura (Department of Hygiene, Kyoto Prefectural University of Medicine) for very helpful experimental advice. This work was supported in part by the Ministry of Education, Culture, Sports, Science and Technology of Japan.
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Horinaka, M., Yoshida, T., Shiraishi, T. et al. Luteolin induces apoptosis via death receptor 5 upregulation in human malignant tumor cells. Oncogene 24, 7180–7189 (2005). https://doi.org/10.1038/sj.onc.1208874
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DOI: https://doi.org/10.1038/sj.onc.1208874
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