title: Understanding of tolerance in TRAIL-induced apoptosis and cancelation of its machinery by α-mangostin, a xanthone derivative.
abstract: Tumor necrosis-factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF-superfamily that selectively induces apoptosis through death receptors (DRs) 4 and/or 5 in cancer cells. These receptors are expressed on the cancer cell surface, without affecting normal cells. Unfortunately, many clinical studies have shown that cancer cells acquire TRAIL-resistance and finally avoid TRAIL-induced apoptosis. The detailed mechanisms of this resistance are not well understood. In the current study, we established a TRAIL-resistant human colon cancer DLD-1 cell line to clarify the mechanisms of TRAIL-resistance and developed agents to cancel its machinery. Also, we found that cancer stem-like cells from breast epithelial proliferating MCF10A cells were also sensitive to TRAIL-induced apoptosis. The enforced expression of DR5 in both TRAIL-resistant cells partially recovered the sensitivity to the TRAIL ligand, which was judged by the activation of caspase-8. As a result, we newly found that the mechanisms of TRAIL-resistance comprised co-existence of a decrease in the expression level of DR5 along with malfunction of its recruitment to the cell surface, as evidenced by Western blot and immunocytological analysis, respectively. Interestingly, α-mangostin, which is a xanthone derivative, canceled the resistance by increasing the expression level of DR5 through down-regulation of miR-133b and effectively induced the translocation of DR5 to the cancer cell surface membrane in TRAIL-resistant DLD-1 cells. These findings indicate that α-mangostin functioned as a sensitizer of TRAIL-induced apoptosis and may thus serve as a possible adjuvant compound for cytokine therapy to conquer TRAIL-resistance.
authors: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Yanagido, Gifu 501-1193, Japan.
authors: Minami
authors: M
authors: Kumazaki
authors: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Yanagido, Gifu 501-1193, Japan.
authors: Haruka
authors: H
authors: Shinohara
authors: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Yanagido, Gifu 501-1193, Japan.
authors: Kohei
authors: K
authors: Taniguchi
authors: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Yanagido, Gifu 501-1193, Japan.
authors: Hiroshi
authors: H
authors: Ueda
authors: Department of Microbiology, Yokohama City University School of Medicine, Yokohama 236-0027, Japan.
authors: Mayuko
authors: M
authors: Nishi
authors: Department of Microbiology, Yokohama City University School of Medicine, Yokohama 236-0027, Japan.
authors: Akihide
authors: A
authors: Ryo
authors: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Yanagido, Gifu 501-1193, Japan.
authors: Yukihiro
authors: Y
authors: Akao
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004789:Enzyme Activation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport; D034622:RNA Interference; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014162:Transfection; D044004:Xanthones / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C548234:MIRN133 microRNA, human; D035683:MicroRNAs; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D044004:Xanthones; C505530:CASP8 protein, human; D053181:Caspase 8; C021053:mangostin
keywords: TRAIL-induced apoptosis; TRAIL-resistance; cancer stem-like cell; miR-133b; α-mangostin