title: Combined treatment with verrucarin A and tumor necrosis factor-α sensitizes apoptosis by overexpression of nuclear factor-kappaB-mediated Fas.
abstract: Verrucarin A (VA) is a member of the family of macrocyclic trichothecenes, which exhibit anti-cancer and immune-modulating activities. However, VA has not yet been demonstrated to be involved in the sensitization of tumor necrosis factor-alpha (TNF-α)-mediated apoptosis. In the present study, we found that VA triggers TNF-α-induced apoptosis in human breast cancer MDA-MB-231 and MCF-7 cells. In particular, activation of caspas-3 and caspase-8 as well as release of cytochrome c were significantly enhanced in response to the combined treatment with VA and TNF-α (VA/TNF-α) and the pan-caspase inhibitor z-VAD-fmk completely reversed the apoptosis, suggesting that caspases are the main effector molecules in VA/TNF-α-induced apoptosis via the intrinsic and extrinsic pathway. Moreover, we confirmed that enhanced Fas expression plays a critical role, because the Fas-blocking antibody partially inhibited VA/TNF-α-induced apoptosis. VA also increased specific DNA-binding activity of nuclear factor-kappaB (NF-κB) via nuclear translocation of p50 and p65. In addition, pretreatment with the NF-κB inhibitor MG132 blocked VA/TNF-α-induced apoptosis by suppression of NF-κB-dependent Fas expression. These results indicated that VA enhances TNF-α-induced apoptosis via NF-κB-dependent Fas overexpression.
authors.affiliation: Laboratory of Immunobiology, Department of Marine Life Sciences, Jeju National University, Ara-1 dong, Jeju 690-756, Republic of Korea.
authors.forename: Rajapaksha Gedara Prasad Tharanga
authors.initials: RGPT
authors.lastname: Jayasooriya
authors.affiliation: Department of Biology Education, Daegu University, Jillyang, Gyeongsan, Gyeongbuk 712-714, Republic of Korea.
authors.forename: Dong-Oh
authors.initials: DO
authors.lastname: Moon
authors.affiliation: Laboratory of Immunobiology, Department of Marine Life Sciences, Jeju National University, Ara-1 dong, Jeju 690-756, Republic of Korea.
authors.forename: Sang Rul
authors.initials: SR
authors.lastname: Park
authors.affiliation: Department of Biochemistry, College of Oriental Medicine, Dong-Eui University, Busan 614-050, Republic of Korea.
authors.forename: Yung Hyun
authors.initials: YH
authors.lastname: Choi
authors.affiliation: Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Chungbuk 363-883, Republic of Korea.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Asami
authors.affiliation: Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Chungbuk 363-883, Republic of Korea.
authors.forename: Mun-Ock
authors.initials: MO
authors.lastname: Kim
authors.affiliation: Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Chungbuk 363-883, Republic of Korea.
authors.forename: Jae-Hyuk
authors.initials: JH
authors.lastname: Jang
authors.affiliation: Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Chungbuk 363-883, Republic of Korea.
authors.forename: Bo Yeon
authors.initials: BY
authors.lastname: Kim
authors.affiliation: Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Chungbuk 363-883, Republic of Korea.
authors.forename: Jong Seog
authors.initials: JS
authors.lastname: Ahn
authors.affiliation: Laboratory of Immunobiology, Department of Marine Life Sciences, Jeju National University, Ara-1 dong, Jeju 690-756, Republic of Korea. Electronic address: immunkim@jejunu.ac.kr.
authors.forename: Gi-Young
authors.initials: GY
authors.lastname: Kim
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000906:Antibodies / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D051996:Transcription Factor RelA / Q000378:metabolism; D014255:Trichothecenes / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation; D019014:fas Receptor / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000906:Antibodies; D061945:Caspase Inhibitors; C491901:FAS protein, human; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; C498143:RELA protein, human; D051996:Transcription Factor RelA; D014255:Trichothecenes; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D045304:Cytochromes c; C505407:CASP3 protein, human; C505530:CASP8 protein, human; D053148:Caspase 3; D053181:Caspase 8; C005348:muconomycin A
keywords: Apoptosis; Fas; Nuclear factor-kappaB; Tumor necrosis factor-α; Verrucarin A