title: Bakuchiol sensitizes cancer cells to TRAIL through ROS- and JNK-mediated upregulation of death receptors and downregulation of survival proteins.
abstract: We investigated whether bakuchiol, an analog of resveratrol enhances the apoptosis ability of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) in cancer cells. Bakuchiol enhanced expression of cell death receptor (DR) in TRAIL-sensitive and -resistant colon cancer cells in a dose-dependent manner. A combination of bakuchiol with TRAIL significantly inhibited cell growth of TRAIL sensitive HCT116 and TRAIL resistant HT-29 cells. The expression of TRAIL receptors; DR4 and DR5 was significantly increased by treatment of bakuchiol, however, the expression of survival proteins (e.g., cFLIP, survivin, XIAP and Bcl2) was suppressed. Moreover, the expression of apoptosis related proteins such as cleaved caspase-3, -8, -9 and PARP was increased by combination treatment of bakuchiol and TRAIL. Depletion of DR4 or DR5 by small interfering RNA significantly reversed the cell growth inhibitory effects of bakuchiol in HCT116 and HT-29 cells. Pretreatment with the c-Jun N-terminal kinase (JNK) inhibitor SP600125 and the reactive oxygen species (ROS) scavenger N-acetylcysteine reduced the bakuchiol induced cell growth inhibitory effects. The collective results suggest that bakuchiol facilitates TRAIL-induced apoptosis in colon cancer cells through up-regulation of the TRAIL receptors; DR4 and DR5 via ROS/JNK pathway signals.
authors.affiliation: The Hormel Institute, University of Minnesota, United States; Division of Life Science, Korea Basic Science Institute, Daejeon, Republic of Korea. Electronic address: pmh5205@gmail.com.
authors.forename: Mi Hee
authors.initials: MH
authors.lastname: Park
authors.affiliation: Botanical Drug Laboratory, Korea Ginseng Corporation, Yuseong-gu, Daejeon, Republic of Korea.
authors.forename: Jong Han
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Division of Life Science, Korea Basic Science Institute, Daejeon, Republic of Korea.
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Chung
authors.affiliation: Botanical Drug Laboratory, Korea Ginseng Corporation, Yuseong-gu, Daejeon, Republic of Korea. Electronic address: fptase@hanmail.net.
authors.forename: Seung Ho
authors.initials: SH
authors.lastname: Lee
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D010636:Phenols / Q000302:isolation & purification / Q000494:pharmacology*; D029907:Psoralea / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000378:metabolism*; D053218:Receptors, Death Domain / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D010636:Phenols; D017382:Reactive Oxygen Species; D053218:Receptors, Death Domain; D053221:TNF-Related Apoptosis-Inducing Ligand; D048670:MAP Kinase Kinase 4; C012765:bakuchiol
keywords: Bakuchiol; Death receptor; JNK; ROS; TRAIL