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RSL3 and Erastin differentially regulate redox signaling to promote Smac mimetic-induced cell death.
Oncotarget. 2016 Sep 27; 7(39):63779-63792.O

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+Show Affiliations

Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany.Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany.Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany.Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany. German Cancer Consortium (DKTK), Heidelberg, Germany. German Cancer Research Center (DKFZ), Heidelberg, Germany.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27588473

Citation

Dächert, Jasmin, et al. "RSL3 and Erastin Differentially Regulate Redox Signaling to Promote Smac Mimetic-induced Cell Death." Oncotarget, vol. 7, no. 39, 2016, pp. 63779-63792.
Dächert J, Schoeneberger H, Rohde K, et al. RSL3 and Erastin differentially regulate redox signaling to promote Smac mimetic-induced cell death. Oncotarget. 2016;7(39):63779-63792.
Dächert, J., Schoeneberger, H., Rohde, K., & Fulda, S. (2016). RSL3 and Erastin differentially regulate redox signaling to promote Smac mimetic-induced cell death. Oncotarget, 7(39), 63779-63792. https://doi.org/10.18632/oncotarget.11687
Dächert J, et al. RSL3 and Erastin Differentially Regulate Redox Signaling to Promote Smac Mimetic-induced Cell Death. Oncotarget. 2016 Sep 27;7(39):63779-63792. PubMed PMID: 27588473.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - RSL3 and Erastin differentially regulate redox signaling to promote Smac mimetic-induced cell death. AU - Dächert,Jasmin, AU - Schoeneberger,Hannah, AU - Rohde,Katharina, AU - Fulda,Simone, PY - 2016/05/03/received PY - 2016/08/11/accepted PY - 2016/9/3/pubmed PY - 2018/4/6/medline PY - 2016/9/3/entrez KW - ROS KW - Smac mimetic KW - cell death KW - ferroptosis KW - redox SP - 63779 EP - 63792 JF - Oncotarget JO - Oncotarget VL - 7 IS - 39 N2 - 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. SN - 1949-2553 UR - https://www.unboundmedicine.com/medline/citation/27588473/RSL3_and_Erastin_differentially_regulate_redox_signaling_to_promote_Smac_mimetic_induced_cell_death_ L2 - http://www.impactjournals.com/oncotarget/misc/linkedout.php?pii=11687 DB - PRIME DP - Unbound Medicine ER -