title: Baicalein overcomes tumor necrosis factor-related apoptosis-inducing ligand resistance via two different cell-specific pathways in cancer cells but not in normal cells.
abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is one of the most promising candidates for new cancer therapeutics. A current problem is that some cancers still remain resistant to TRAIL. We show for the first time that a naturally occurring flavonoid, baicalein, overcomes TRAIL resistance in cancer cells. The combination of baicalein and TRAIL effectively induced apoptosis in TRAIL-resistant colon cancer SW480 cells. Baicalein up-regulated the expression of death receptor 5 (DR5) among TRAIL receptors at the mRNA and protein levels. Suppression of this up-regulation with small interfering RNA (siRNA) efficiently reduced the apoptosis induced by TRAIL and baicalein, suggesting that the sensitization was mediated through DR5 induction. Moreover, baicalein also overcame TRAIL resistance with DR5 up-regulation in prostate cancer PC3 cells. Of note, the combination of TRAIL and baicalein hardly induced apoptosis in normal human cells, such as blood cells and hepatocytes. Baicalein increased DR5 promoter activity, and this enhanced activity was diminished by mutation of a CCAAT/enhancer-binding protein homologous protein (CHOP)-binding site in SW480 cells. In SW480 cells, CHOP siRNA blocked both functions of baicalein. CHOP expression was induced by baicalein in SW480 cells; however, in PC3 cells, baicalein scarcely induced CHOP and mutation of the CHOP-binding site did not abrogate the DR5 promoter activation by baicalein. Interestingly, baicalein induced reactive oxygen species (ROS) and a ROS scavenger prevented DR5 expression and TRAIL sensitization in PC3 but not SW480 cells. These results indicate that, using two different pathways, baicalein exposes cancer surveillance of TRAIL and overcomes TRAIL resistance in cancer cells.
authors.affiliation: Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kyoto, Japan.
authors.forename: Hiroya
authors.initials: H
authors.lastname: Taniguchi
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Yoshida
authors.forename: Mano
authors.initials: M
authors.lastname: Horinaka
authors.forename: Takashi
authors.initials: T
authors.lastname: Yasuda
authors.forename: Ahmed E
authors.initials: AE
authors.lastname: Goda
authors.forename: Masako
authors.initials: M
authors.lastname: Konishi
authors.forename: Miki
authors.initials: M
authors.lastname: Wakada
authors.forename: Keisho
authors.initials: K
authors.lastname: Kataoka
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakai
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015536:Down-Regulation; D044950:Flavanones / Q000494:pharmacology*; D006801:Humans; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000502:physiology*; D051742:Transcription Factor CHOP / Q000378:metabolism
chemical_list: C497249:DDIT3 protein, human; D044950:Flavanones; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D051742:Transcription Factor CHOP; C006680:baicalein