title: Depolarization potentiates TRAIL-induced apoptosis in human melanoma cells: role for ATP-sensitive K+ channels and endoplasmic reticulum stress.
abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is promising             for cancer treatment owing to its selective cytotoxicity against malignant cells.             However, some cancer cell types, including malignant melanoma cells, are resistant             to TRAIL-induced apoptosis. Therefore, drugs that can amplify TRAIL cytotoxicity             are urgently required. Depolarization of the plasma membrane potential is associated             with apoptosis induced by a variety of death-inducing agents but its role in apoptosis             remains a matter of debate. We found that TRAIL treatment resulted in robust depolarization             in human melanoma cells with a considerable lag (2-4 h). Moreover, membrane-depolarizing             agents, including K+ and ATP-sensitive K+ (KATP) channel inhibitors glibenclamide             and U37883A enhanced TRAIL-induced apoptosis. On the contrary, inhibitors of calcium-             and voltage-dependent K+ channels and mitochondrial KATP channels had no such             effects. Melanocytes were insensitive to TRAIL-induced depolarization and apoptosis             as well as to the sensitization by membrane-depolarizing agents despite their             substantial surface expression of death receptors. TRAIL induced robust activation             of X-box-binding protein-1 and caspase-12, both of which were enhanced by the             K+ and KATP channel inhibitors, but not by other K+ channel inhibitors. Finally,             caspase-12-selective inhibitor completely abolished the amplification of apoptosis.             These findings suggest that depolarization promotes endoplasmic reticulum stress-mediated             death pathway, thereby amplifying TRAIL cytotoxicity. Thus, membrane-depolarizing             agents such as KATP channel inhibitors may have therapeutic potential in the treatment             of TRAIL-resistant cancer cells without impairing tumor-selectivity.
authors.affiliation: Nihon University Graduate School of Medical Science, Tokyo, Japan. suzuki.yoshihiro@nihon-u.ac.jp
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Toshio
authors.initials: T
authors.lastname: Inoue
authors.forename: Mayumi
authors.initials: M
authors.lastname: Murai
authors.forename: Miki
authors.initials: M
authors.lastname: Suzuki-Karasaki
authors.forename: Toyoko
authors.initials: T
authors.lastname: Ochiai
authors.forename: Chisei
authors.initials: C
authors.lastname: Ra
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053454:Caspase 12 / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D004789:Enzyme Activation; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D054086:KATP Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008544:Melanocytes / Q000187:drug effects; D008545:Melanoma; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D009025:Morpholines / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism / Q000502:physiology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D054086:KATP Channels; D009025:Morpholines; D026902:Potassium Channel Blockers; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C082658:U 37883A; C506444:CASP12 protein, human; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053454:Caspase 12; D053148:Caspase 3; D053179:Caspase 7; D000218:Adamantane; D011188:Potassium; D005905:Glyburide