title: RSL3 and Erastin differentially regulate redox signaling to promote Smac mimetic-induced cell death.
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.
authors: Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany.
authors: Jasmin
authors: J
authors: Dächert
authors: Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany.
authors: Hannah
authors: H
authors: Schoeneberger
authors: Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany.
authors: Katharina
authors: K
authors: Rohde
authors: Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Simone
authors: S
authors: Fulda
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D002243:Carbolines / Q000494:pharmacology*; D016923:Cell Death; D003676:Deferoxamine / Q000494:pharmacology; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D020868:Gene Silencing; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007501:Iron / Q000378:metabolism; D015227:Lipid Peroxidation; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D010084:Oxidation-Reduction; D010879:Piperazines / Q000494:pharmacology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D051017:Apoptosis Regulatory Proteins; D002243:Carbolines; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D010879:Piperazines; C587550:RSL3 compound; D017382:Reactive Oxygen Species; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C477224:erastin; D007501:Iron; D003676:Deferoxamine
keywords: ROS; Smac mimetic; cell death; ferroptosis; redox