title: Ferroptosis is induced following siramesine and lapatinib treatment of breast cancer cells.
abstract: Ferroptosis is an iron-dependent, oxidative cell death, and is distinct from apoptosis, necrosis and autophagy. In this study, we demonstrated that lysosome disrupting agent, siramesine and a tyrosine kinase inhibitor, lapatinib synergistically induced cell death and reactive oxygen species (ROS) in MDA MB 231, MCF-7, ZR-75 and SKBr3 breast cancer cells over a 24 h time course. Furthermore, the iron chelator deferoxamine (DFO) significantly reduced cytosolic ROS and cell death following treatment with siramesine and lapatinib. Furthermore, we determined that FeCl3 levels were elevated in cells treated with siramesine and lapatinib indicating an iron-dependent cell death, ferroptosis. To confirm this, we treated cells with a potent inhibitor of ferroptosis, ferrastatin-1 that effectively inhibited cell death following siramesine and lapatinib treatment. The increase levels of iron could be due to changes in iron transport. We found that the expression of transferrin, which is responsible for the transport of iron into cells, is increased following treatment with lapatinib alone or in combination with siramesine. Knocking down of transferrin resulted in decreased cell death and ROS after treatment. In addition, ferroportin-1 (FPN) is an iron transport protein, responsible for removal of iron from cells. We found its expression is decreased after treatment with siramesine alone or in combination with lapatinib. Overexpression FPN resulted in decreased ROS and cell death whereas knockdown of FPN increased cell death after siramesine and lapatinib treatment. This indicates a novel induction of ferroptosis through altered iron regulation by treating breast cancer cells with a lysosome disruptor and a tyrosine kinase inhibitor.
authors.affiliation: Research Institute in Oncology and Hematology, CancerCare Manitoba, University of Manitoba, Winnipeg, MB, Canada R3E OV9.|Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, Canada R3E 0J9.|Key Laboratory of Radiobiology (Ministry of Health), School of Public Health, Jilin University, 1163 Xinmin Street, Changchun 130021, Jilin, China.
authors.forename: S
authors.initials: S
authors.lastname: Ma
authors.affiliation: Research Institute in Oncology and Hematology, CancerCare Manitoba, University of Manitoba, Winnipeg, MB, Canada R3E OV9.
authors.forename: E S
authors.initials: ES
authors.lastname: Henson
authors.affiliation: Research Institute in Oncology and Hematology, CancerCare Manitoba, University of Manitoba, Winnipeg, MB, Canada R3E OV9.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Research Institute in Oncology and Hematology, CancerCare Manitoba, University of Manitoba, Winnipeg, MB, Canada R3E OV9.|Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, Canada R3E 0J9.
authors.forename: S B
authors.initials: SB
authors.lastname: Gibson
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D003514:Cyclohexylamines / Q000494:pharmacology; D003676:Deferoxamine / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D005293:Ferritins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology; D000077341:Lapatinib; D008247:Lysosomes / Q000187:drug effects; D061986:MCF-7 Cells; D010655:Phenylenediamines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000819:agonists* / Q000378:metabolism; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013141:Spiro Compounds / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014168:Transferrin / Q000235:genetics / Q000378:metabolism; D000098742:Ferroportin
chemical_list: D000970:Antineoplastic Agents; D027682:Cation Transport Proteins; D003514:Cyclohexylamines; C110547:DMRT1 protein; D007093:Imidazoles; D007211:Indoles; D007502:Iron Chelating Agents; C109644:Lu 28-179; D010655:Phenylenediamines; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D017382:Reactive Oxygen Species; D011990:Receptors, Transferrin; D013141:Spiro Compounds; D014157:Transcription Factors; D014168:Transferrin; C573944:ferrostatin-1; D000098742:Ferroportin; C507699:necrostatin-1; D000077341:Lapatinib; D005293:Ferritins; D007501:Iron; D003676:Deferoxamine