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Mutant p53 reactivators protect breast cancer cells from ferroptosis
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  • William R. Taylor,
  • Dewmi Sandaru Rathnayake,
  • Samkeliso Dlamini,
  • Kadry Elkalawozgy,
  • L. M. Viranga Tillekeratne
William R. Taylor
The University of Toledo

Corresponding Author:william.taylor3@utoledo.edu

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Dewmi Sandaru Rathnayake
The University of Toledo
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Samkeliso Dlamini
The University of Toledo
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Kadry Elkalawozgy
The University of Toledo
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L. M. Viranga Tillekeratne
The University of Toledo
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Abstract

Abstract. Ferroptosis is a novel non-apoptotic form of cell death characterized by iron-dependent reactive oxygen species (ROS)-mediated lipid peroxidation. In several different cell systems, the tumor suppressor p53 can enhance sensitivity to ferroptotic inducers. At least half of all human cancers show loss of function of p53. Furthermore, many of those tumors express mutant forms of p53 that has lost its wild-type function. Several groups have designed small molecules that can reactivate the wild-type function of these missense p53 mutants. We reasoned that p53 reactivators may also enhances sensitivity of certain cancer cells to ferroptosis stimuli. To test this idea we combined a number of different p53 reactivators with small molecule inducers of ferroptosis. In contrast, we observed that several p53 reactivators protected cells from cell death induced by ferroptotic inducers. Suprisingly, this protection still occurred in p53-null cell lines. We observed that these reactivators were neither free radical scavengers nor ion chelators. One of these p53 reactivator molecules, NSC 59984, reduced expression of GPX4, which is unlikely to explain the ability to reduced sensitivity to ferroptosis. We suggested that these p53 reactivators function via an unknown, p53-independent manner to suppress ferroptosis.
10 Feb 2024Submitted to Cell Biochemistry & Function
21 Feb 2024Submission Checks Completed
21 Feb 2024Assigned to Editor
21 Feb 2024Review(s) Completed, Editorial Evaluation Pending
16 Mar 2024Editorial Decision: Revise Major
12 Apr 20241st Revision Received
15 Apr 2024Submission Checks Completed
15 Apr 2024Assigned to Editor
15 Apr 2024Review(s) Completed, Editorial Evaluation Pending
15 Apr 2024Reviewer(s) Assigned
21 Apr 2024Editorial Decision: Accept
27 Apr 2024Review(s) Completed, Editorial Evaluation Pending
27 Apr 2024Submission Checks Completed
27 Apr 2024Assigned to Editor
29 Apr 2024Editorial Decision: Accept