title: Distinct effects of TRAIL on the mitochondrial network in human cancer cells and normal cells: role of plasma membrane depolarization.
abstract: Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) is a promising anticancer drug due to its tumor-selective cytotoxicity. Here we report that TRAIL exhibits distinct effects on the mitochondrial networks in malignant cells and normal cells. Live-cell imaging revealed that multiple human cancer cell lines and normal cells exhibited two different modes of mitochondrial responses in response to TRAIL and death receptor agonists. Mitochondria within tumor cells became fragmented into punctate and clustered in response to toxic stimuli. The mitochondrial fragmentation was observed at 4 h, then became more pronounced over time, and associated with apoptotic cell death. In contrast, mitochondria within normal cells such as melanocytes and fibroblasts became only modestly truncated, even when they were treated with toxic stimuli. Although TRAIL activated dynamin-related protein 1 (Drp1)-dependent mitochondrial fission, inhibition of this process by Drp1 knockdown or with the Drp1 inhibitor mdivi-1, potentiated TRAIL-induced apoptosis, mitochondrial fragmentation, and clustering. Moreover, mitochondrial reactive oxygen species (ROS)-mediated depolarization accelerated mitochondrial network abnormalities in tumor cells, but not in normal cells, and TRAIL caused higher levels of mitochondrial ROS accumulation and depolarization in malignant cells than in normal cells. Our findings suggest that tumor cells are more prone than normal cells to oxidative stress and depolarization, thereby being more vulnerable to mitochondrial network abnormalities and that this vulnerability may be relevant to the tumor-targeting killing by TRAIL.
authors.affiliation: Division of Physiology, Department of Biomedical Sciences, Nihon University School of Medicine, Tokyo, Japan.|Innovative Therapy Research Group, Nihon University Research Institute of Medical Science, Tokyo, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Suzuki-Karasaki
authors.affiliation: Innovative Therapy Research Group, Nihon University Research Institute of Medical Science, Tokyo, Japan.|Division of General Medicine, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Fujiwara
authors.affiliation: Innovative Therapy Research Group, Nihon University Research Institute of Medical Science, Tokyo, Japan.|Division of General Medicine, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Saito
authors.affiliation: Department of Dermatology, Nihon University Surugadai Hospital, Tokyo, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Suzuki-Karasaki
authors.affiliation: Department of Dermatology, Nihon University Surugadai Hospital, Tokyo, Japan.
authors.forename: Toyoko
authors.initials: T
authors.lastname: Ochiai
authors.affiliation: Innovative Therapy Research Group, Nihon University Research Institute of Medical Science, Tokyo, Japan.|Division of General Medicine, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Soma
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress; D052999:Quinazolinones / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000737:chemistry*
chemical_list: C549041:3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D052999:Quinazolinones; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D053148:Caspase 3; D053179:Caspase 7; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins
keywords: TRAIL; depolarization; mitochondrial fragmentation; reactive oxygen species; tumor-selective killing