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Luteolin induces apoptosis via death receptor 5 upregulation in human malignant tumor cells

Oncogene volume 24, pages 7180–7189 (2005)Cite this article

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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Authors and Affiliations

  1. Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, 602-8566, Kyoto, Japan

    Mano Horinaka, Tatsushi Yoshida, Takumi Shiraishi, Susumu Nakata, Miki Wakada, Ryoko Nakanishi & Toshiyuki Sakai

  2. Department of Applied Biochemistry, Kyoto Prefectural University, Shimogamo, Sakyo-ku, 606-8522, Kyoto, Japan

    Mano Horinaka & Hiroshi Matsui

  3. Department of Urology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, 602-8566, Kyoto, Japan

    Takumi Shiraishi

  4. Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, 602-8566, Kyoto, Japan

    Hoyoku Nishino

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  1. Mano Horinaka
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Correspondence to Toshiyuki Sakai.

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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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