title: Downregulation of Nrf2 by the combination of TRAIL and Valproic acid induces apoptotic cell death of TRAIL-resistant papillary thyroid cancer cells via suppression of Bcl-xL.
abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) represents an effective agent for the treatment of many cancers, though the majority of thyroid cancers are found to be resistant. Therefore it would be necessary to identify agents capable of increasing the sensitivity of these cancers to TRAIL-mediated cell death. Here, we examined the therapeutic effect and its underlying mechanism of combination treatment of TRAIL and histone deacetylase inhibitor, Valproic acid (VPA) in vitro using human papillary thyroid cancer (PTC) cells and in vivo using an orthotopic mouse model of PTC. TRAIL-VPA combination therapy synergistically induced apoptotic cell death in TRAIL-resistant PTC through caspase activation. In addition, downregulation of antioxidant transcription factor, Nrf2 by co-treatment of TRAIL-VPA induces cell death via suppression of Bcl-xL in vitro and in vivo; these effects were further enhanced following siRNA inhibition of these proteins in combination with TRAIL or TRAIL-VPA. Taken together, VPA sensitized TRAIL-resistant PTC cells to apoptotic cell death through involvement of Nrf2 and Bcl-xL. Thus, the combination of VPA and TRAIL may be a promising therapy for TRAIL-resistant PTC.
authors.affiliation: Department of Otolaryngology, School of Medicine, Ajou University, Suwon, Republic of Korea.
authors.forename: Hyun-Young
authors.initials: HY
authors.lastname: Cha
authors.affiliation: Department of Otolaryngology, School of Medicine, Ajou University, Suwon, Republic of Korea.
authors.forename: Bok-Soon
authors.initials: BS
authors.lastname: Lee
authors.affiliation: Department of Otolaryngology, School of Medicine, Ajou University, Suwon, Republic of Korea.
authors.forename: Jae Won
authors.initials: JW
authors.lastname: Chang
authors.affiliation: Department of Otolaryngology, School of Medicine, Ajou University, Suwon, Republic of Korea; Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea.
authors.forename: Ju Kyeong
authors.initials: JK
authors.lastname: Park
authors.affiliation: Department of Pathology, School of Medicine, Ajou University, Suwon, Republic of Korea.
authors.forename: Jae Ho
authors.initials: JH
authors.lastname: Han
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea.
authors.forename: Yong-Sung
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Department of Otolaryngology, School of Medicine, Ajou University, Suwon, Republic of Korea.
authors.forename: Yoo Seob
authors.initials: YS
authors.lastname: Shin
authors.affiliation: Department of Otorhinolaryngology, College of Medicine, Yonsei University, Seoul, Republic of Korea.
authors.forename: Hyung Kwon
authors.initials: HK
authors.lastname: Byeon
authors.affiliation: Department of Otolaryngology, School of Medicine, Ajou University, Suwon, Republic of Korea; Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea. Electronic address: ostium@ajou.ac.kr.
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Kim
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002291:Carcinoma, Papillary; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014162:Transfection; D014635:Valproic Acid / Q000494:pharmacology*; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D056572:Histone Deacetylase Inhibitors; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495636:Nfe2l2 protein, mouse; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D051020:bcl-X Protein; D014635:Valproic Acid
keywords: Bcl-xL; Nrf2; Papillary thyroid cancer; TRAIL; TRAIL-resistant; Valproic acid