Oncotarget

Research Papers:

RSL3 and Erastin differentially regulate redox signaling to promote Smac mimetic-induced cell death

Jasmin Dächert, Hannah Schoeneberger, Katharina Rohde and Simone Fulda _

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Oncotarget. 2016; 7:63779-63792. https://doi.org/10.18632/oncotarget.11687

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Abstract

Jasmin Dächert1,*, Hannah Schoeneberger1,*, Katharina Rohde1, Simone Fulda1,2,3

1Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany

2German Cancer Consortium (DKTK), Heidelberg, Germany

3German Cancer Research Center (DKFZ), Heidelberg, Germany

*Shared first authorship

Correspondence to:

Simone Fulda, email: [email protected]

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.


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