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

Mano Horinaka; Tatsushi Yoshida; Takumi Shiraishi; Susumu Nakata; Miki Wakada; Ryoko Nakanishi; Hoyoku Nishino; Hiroshi Matsui; Toshiyuki Sakai

doi:10.1038/sj.onc.1208874

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

Oncogene. 2005 Nov 3;24(48):7180-9. doi: 10.1038/sj.onc.1208874.

Authors

Mano Horinaka¹, Tatsushi Yoshida, Takumi Shiraishi, Susumu Nakata, Miki Wakada, Ryoko Nakanishi, Hoyoku Nishino, Hiroshi Matsui, Toshiyuki Sakai

Affiliation

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

PMID: 16007131
DOI: 10.1038/sj.onc.1208874

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.

Oncogene (2005) 24, 7180-7189. doi:10.1038/sj.onc.1208874; published online 11 July 2005.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis / drug effects*
BH3 Interacting Domain Death Agonist Protein / metabolism
Blotting, Western
Caspase Inhibitors
Cell Line, Tumor
Dose-Response Relationship, Drug
Enzyme Activation / drug effects
Enzyme Inhibitors / pharmacology
Gene Expression Regulation, Neoplastic / drug effects*
HeLa Cells
Humans
Luciferases / metabolism
Luteolin / pharmacology*
Male
Promoter Regions, Genetic
Prostatic Neoplasms / pathology
Proto-Oncogene Proteins c-bcl-2 / metabolism
RNA, Messenger / metabolism
RNA, Small Interfering / metabolism
Receptors, TNF-Related Apoptosis-Inducing Ligand
Receptors, Tumor Necrosis Factor / genetics
Receptors, Tumor Necrosis Factor / metabolism*
Recombinant Proteins / metabolism
Up-Regulation / drug effects*

Substances

BH3 Interacting Domain Death Agonist Protein
Caspase Inhibitors
Enzyme Inhibitors
Proto-Oncogene Proteins c-bcl-2
RNA, Messenger
RNA, Small Interfering
Receptors, TNF-Related Apoptosis-Inducing Ligand
Receptors, Tumor Necrosis Factor
Recombinant Proteins
TNFRSF10A protein, human
TNFRSF10B protein, human
Luciferases
Luteolin