title: Inhibition of Lon protease by triterpenoids alters mitochondria and is associated to cell death in human cancer cells.
abstract: Mitochondrial Lon protease (Lon) regulates several mitochondrial functions, and is inhibited by the anticancer molecule triterpenoid 2-cyano-3, 12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO), or by its C-28 methyl ester derivative (CDDO-Me). To analyze the mechanism of action of triterpenoids, we investigated intramitochondrial reactive oxygen species (ROS), mitochondrial membrane potential, mitochondrial mass, mitochondrial dynamics and morphology, and Lon proteolytic activity in RKO human colon cancer cells, in HepG2 hepatocarcinoma cells and in MCF7 breast carcinoma cells. We found that CDDO and CDDO-Me are potent stressors for mitochondria in cancer cells, rather than normal non-transformed cells. In particular, they: i) cause depolarization; ii) increase mitochondrial ROS, iii) alter mitochondrial morphology and proteins involved in mitochondrial dynamics; iv) affect the levels of Lon and those of aconitase and human transcription factor A, which are targets of Lon activity; v) increase level of protein carbonyls in mitochondria; vi) lead to intrinsic apoptosis. The overexpression of Lon can rescue cells from cell death, providing an additional evidence on the role of Lon in conditions of excessive stress load.
authors: Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors: Lara
authors: L
authors: Gibellini
authors: Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors: Marcello
authors: M
authors: Pinti
authors: Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors: Regina
authors: R
authors: Bartolomeo
authors: Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors: Sara
authors: S
authors: De Biasi
authors: Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari, Bari, Italy.
authors: Antonella
authors: A
authors: Cormio
authors: CNR - Institute of Biomembranes and Bioenergetics, Bari, Italy.
authors: Clara
authors: C
authors: Musicco
authors: Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors: Gianluca
authors: G
authors: Carnevale
authors: Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors: Simone
authors: S
authors: Pecorini
authors: Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors: Milena
authors: M
authors: Nasi
authors: Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors: Anto
authors: A
authors: De Pol
authors: Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors: Andrea
authors: A
authors: Cossarizza
mesh_terms: D049069:ATP-Dependent Proteases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000154:Aconitate Hydratase / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D056945:Hep G2 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D061986:MCF-7 Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D063154:Mitochondrial Dynamics / Q000187:drug effects; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D011480:Protease Inhibitors / Q000494:pharmacology*; D050050:Protein Carbonylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; D011480:Protease Inhibitors; C499631:TFAM protein, human; D014157:Transcription Factors; D013481:Superoxides; D009828:Oleanolic Acid; D006861:Hydrogen Peroxide; C445068:bardoxolone methyl; D049069:ATP-Dependent Proteases; C000595973:LONP1 protein, human; D000154:Aconitate Hydratase
keywords: CDDO; CDDO-Me; Lon; mitochondria