RSL3 and Erastin differentially regulate redox signaling to promote Smac mimetic-induced cell death
| Autor: | Katharina Rohde, Simone Fulda, Jasmin Dächert, Hannah Schoeneberger |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
Smac mimetic
0301 basic medicine Programmed cell death Iron Apoptosis Oxidative phosphorylation Deferoxamine GPX4 Piperazines Amino Acid Chloromethyl Ketones Mitochondrial Proteins Lipid peroxidation 03 medical and health sciences chemistry.chemical_compound Humans Gene Silencing Caspase chemistry.chemical_classification Reactive oxygen species Cell Death biology Gene Expression Regulation Leukemic Intracellular Signaling Peptides and Proteins ROS Glutathione Precursor Cell Lymphoblastic Leukemia-Lymphoma ferroptosis Mitochondria Cell biology 030104 developmental biology Oncology chemistry redox biology.protein Lipid Peroxidation Signal transduction Apoptosis Regulatory Proteins Reactive Oxygen Species Oxidation-Reduction Research Paper Carbolines Signal Transduction |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.11687 |
| Popis: | // Jasmin Dachert 1, * , Hannah Schoeneberger 1, * , Katharina Rohde 1 , Simone Fulda 1, 2, 3 1 Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany 2 German Cancer Consortium (DKTK), Heidelberg, Germany 3 German Cancer Research Center (DKFZ), Heidelberg, Germany * Shared first authorship Correspondence to: Simone Fulda, email: simone.fulda@kgu.de Keywords: Smac mimetic, cell death, ferroptosis, redox, ROS Received: May 03, 2016 Accepted: August 11, 2016 Published: August 29, 2016 ABSTRACT Redox mechanisms play an important role in the control of various signaling pathways. Here, we report that Second mitochondrial activator of caspases (Smac) mimetic-induced cell death is regulated by redox signaling. We show that RSL3, a glutathione (GSH) peroxidase (GPX) 4 inhibitor, or Erastin, an inhibitor of the cystine/glutamate antiporter, cooperate with the Smac mimetic BV6 to induce reactive oxygen species (ROS)-dependent cell death in acute lymphoblastic leukemia (ALL) cells. Addition of the caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk) fails to rescue ROS-induced cell death, demonstrating that RSL3/BV6- or Erastin/BV6-induced cell death occurs in a caspase-independent manner. Interestingly, the iron chelator Deferoxamine (DFO) significantly inhibits RSL3/BV6-induced cell death, whereas it is unable to rescue cell death by Erastin/BV6, showing that RSL3/BV6-, but not Erastin/BV6-mediated cell death depends on iron. ROS production is required for both RSL3/BV6- and Erastin/BV6-induced cell death, since the ROS scavenger α-tocopherol (α-Toc) rescues RSL3/BV6- and Erastin/BV6-induced cell death. By comparison, genetic or pharmacological inhibition of lipid peroxidation by GPX4 overexpression or ferrostatin (Fer)-1 significantly decreases RSL3/BV6-, but not Erastin/BV6-induced cell death, despite inhibition of lipid peroxidation upon exposure to RSL3/BV6 or Erastin/BV6. Of note, inhibition of lipid peroxidation by Fer-1 protects from RSL3/BV6-, but not from Erastin/BV6-stimulated ROS production, indicating that other forms of ROS besides lipophilic ROS occur during Erastin/BV6-induced cell death. Taken together, RSL3/BV6 and Erastin/BV6 differentially regulate redox signaling and cell death in ALL cells. While RSL3/BV6 cotreatment induces ferroptotic cell death, Erastin/BV6 stimulates oxidative cell death independently of iron. These findings have important implications for the therapeutic targeting of redox signaling to enhance Smac mimetic-induced cell death in ALL. |
| Databáze: | OpenAIRE |
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