title: Involvement of p53 in cell death following cell cycle arrest and mitotic catastrophe induced by rotenone.
abstract: In order to investigate the cell death-inducing effects of rotenone, a plant extract commonly used as a mitochondrial complex I inhibitor, we studied cancer cell lines with different genetic backgrounds. Rotenone inhibits cell growth through the induction of cell death and cell cycle arrest, associated with the development of mitotic catastrophe. The cell death inducer staurosporine potentiates the inhibition of cell growth by rotenone in a dose-dependent synergistic manner. The tumor suppressor p53 is involved in rotenone-induced cell death, since the drug treatment results in increased expression, phosphorylation and nuclear localization of the protein. The evaluation of the effects of rotenone on a p53-deficient cell line revealed that although not required for the promotion of mitotic catastrophe, functional p53 appears to be essential for the extensive cell death that occurs afterwards. Our results suggest that mitotic slippage also occurs subsequently to the rotenone-induced mitotic arrest and cells treated with the drug for a longer period become senescent. Treatment of mtDNA-depleted cells with rotenone induces cell death and cell cycle arrest as in cells containing wild-type mtDNA, but not formation of reactive oxygen species. This suggests that the effects of rotenone are not dependent from the production of reactive oxygen species. This work highlights the multiple effects of rotenone in cancer cells related to its action as an anti-mitotic drug.
authors.affiliation: IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua do Campo Alegre 823, 4150-180 Porto, Portugal. apgoncalves@ibmc.up.pt
authors.forename: António Pedro
authors.initials: AP
authors.lastname: Gonçalves
authors.forename: Valdemar
authors.initials: V
authors.lastname: Máximo
authors.forename: Jorge
authors.initials: J
authors.lastname: Lima
authors.forename: Keshav K
authors.initials: KK
authors.lastname: Singh
authors.forename: Paula
authors.initials: P
authors.lastname: Soares
authors.forename: Arnaldo
authors.initials: A
authors.lastname: Videira
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007887:Fabaceae / Q000737:chemistry; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology*; D019311:Staurosporine / Q000494:pharmacology; D013964:Thyroid Neoplasms / Q000188:drug therapy; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D014475:Uncoupling Agents; D012402:Rotenone; D019311:Staurosporine