title: Selenite induces DNA damage and specific mitochondrial degeneration in human bladder cancer cells.
abstract: We have investigated the cytotoxicity and specific effects of selenite in human bladder cancer cell line RT-112 and its clonogenic variant RT-112 HB. Selenite inhibited cell growth and proliferation in both cell lines. Treated cells developed extensive vacuolization which was dose independent but occurring in differing time frames. Ultrastructure analysis revealed that the observed vacuoles are damaged mitochondria and potentially other subcellular compartments. Selenite-specific effects on mitochondria were further confirmed by mitochondrial membrane potential analysis, changes in ATP production and generation of superoxide. Simultaneously, selenite induced DNA damage in treated cells with activation of p53, PARP-1 and JNK and suppressed autophagy. Cells ultimately died via a combination of apoptosis, necrosis and a distinct type of cell death featuring "vacuolar shrinkage", loss of adherence and absence of secondary necrosis as well as other classical markers of either apoptosis or autophagy. The significant presence of so called necroptosis was also not confirmed as the specific inhibitor necrostatin-1 could not prevent cell death. These results thus confirm the toxicity of selenite in bladder cancer cells while pointing at potentially new mechanism of action of this compound in this model.
authors.affiliation: Department of Medical Biology and Genetics, Charles University in Prague, Faculty of Medicine in Hradec Králové, Šimkova 870, 500 38 Hradec Králové, Czech Republic.
authors.forename: K
authors.initials: K
authors.lastname: Řezáčová
authors.affiliation: Department of Medical Biology and Genetics, Charles University in Prague, Faculty of Medicine in Hradec Králové, Šimkova 870, 500 38 Hradec Králové, Czech Republic.
authors.forename: K
authors.initials: K
authors.lastname: Čáňová
authors.affiliation: Department of Medcial Biophysics Charles, University in Prague, Faculty of Medicine in Hradec Králové, Šimkova 870, 500 38 Hradec Králové, Czech Republic.
authors.forename: A
authors.initials: A
authors.lastname: Bezrouk
authors.affiliation: Department of Medical Biology and Genetics, Charles University in Prague, Faculty of Medicine in Hradec Králové, Šimkova 870, 500 38 Hradec Králové, Czech Republic. Electronic address: rudolf@lfhk.cuni.cz.
authors.forename: E
authors.initials: E
authors.lastname: Rudolf
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004249:DNA Damage; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D009336:Necrosis / Q000139:chemically induced; D020887:Selenious Acid / Q000633:toxicity*; D013481:Superoxides / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000378:metabolism / Q000473:pathology*
chemical_list: D016159:Tumor Suppressor Protein p53; D013481:Superoxides; D020887:Selenious Acid
keywords: Bladder cancer; DNA damage; Mitochondria; Necroptosis; Necrosis; Selenite