Amino Acid Withdrawal Engages ATF4-mediated Transsulfuration and Protects Cancer Cells from Oxidative Death

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Abstract/Contents

Abstract: Ferroptosis is a form of regulated cell death which can be triggered by starvation of the amino acid cysteine. Its role in human physiology is poorly understood, but evidence suggests some tumor suppressors act by restricting cellular import of cysteine, thus inducing ferroptosis and preventing cancer growth. Here, I show that the supraphysiologic concentration of arginine in culture medium promotes sensitivity to ferroptosis, and that tumor-physiologic levels of arginine do not permit ferroptosis induction by cysteine starvation. This was observed in a broad panel of cancer cell lines, but not in two non-cancer cell lines. Mechanistically, arginine withdrawal induces Activating Transcription Factor 4 (ATF4) expression, which drives de novo cysteine biosynthesis via the transsulfuration pathway. Treatment with the transsulfuration inhibitor propargylglycine abrogated the protective effects of arginine starvation and direct ATF4 stimulation with thapsigargin also suppressed ferroptosis. Thus, cysteine interconversion from methionine downstream of cystine import suppresses ferroptosis. These data suggest a mechanism by which ATF4 permits cancer cell evasion of tumor suppressive, non-apoptotic cell death. Inhibitors of ATF4 or transsulfuration should be evaluated for their ability to slow tumor growth and induce cancer cell ferroptosis in in vivo models.

Type of resource	text
Date created	June 2019

Author	Poltorack, Carson
Primary advisor	Dixon, Scott
Advisor	Gozani, Or
Degree granting institution	Stanford University, Department of Biology, 2019

Related Publication	Conlon MM, Poltorack CD, Forcina GC* et al (2019). A Compendium of Cell Death Modulators Identifies Regulators of Ferroptosis. In Preparation.
Location	https://purl.stanford.edu/wy495bb1751

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Preferred Citation: Poltorack CD & Dixon SJ (2019). Amino Acid Withdrawal Engages ATF4-mediated Transsulfuration and Protects Cancer Cells from Oxidative Death. Stanford Digital Repository. Available at: https://purl.stanford.edu/wy495bb1751

Undergraduate Theses, Department of Biology, 2018-2019

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