title: SERPINB3 protects from oxidative damage by chemotherapeutics through inhibition of mitochondrial respiratory complex I.
abstract: SERPINB3 (SB3) is a serine protease inhibitor overexpressed in several malignancies of epithelial origin, including primary liver cancer, where it inhibits apoptosis through poorly defined mechanisms. In the present study we analyze the effect of SB3 on hepatoma cell death elicited by a panel of chemotherapeutic agents. We report that SB3 shields cells from the toxicity of drugs with a pro-oxidant action such as doxorubicin, cisplatin and EM20-25. The rapid rise in ROS levels prompted by these compounds causes opening of the mitochondrial permeability transition pore (PTP), irreversibly committing cells to death. We find that a fraction of SB3 locates in mitochondrial inner compartments, and that this mitochondrial fraction increases under conditions of oxidative stress. Mitochondrial SB3 inhibits ROS generation and the ensuing PTP induction and cell death through an inhibitory interaction with respiratory Complex I. These findings identify a novel mechanism of action of SB3 that contributes to tumor cell resistance to anti-neoplastic drugs.
authors.affiliation: CNR Institute of Neuroscience and Department of Biomedical Sciences, University of Padova, Padova, Italy;
authors.forename: Francesco
authors.initials: F
authors.lastname: Ciscato
authors.forename: Marco
authors.initials: M
authors.lastname: Sciacovelli
authors.forename: Gianmarco
authors.initials: G
authors.lastname: Villano
authors.forename: Cristian
authors.initials: C
authors.lastname: Turato
authors.forename: Paolo
authors.initials: P
authors.lastname: Bernardi
authors.forename: Andrea
authors.initials: A
authors.lastname: Rasola
authors.forename: Patrizia
authors.initials: P
authors.lastname: Pontisso
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D020013:Calcium Signaling; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects; D000083162:Mitochondrial Permeability Transition Pore; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015843:Serpins / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species; D015843:Serpins; C051072:squamous cell carcinoma-related antigen; D042967:Electron Transport Complex I