Amino acid restriction sensitizes lung cancer cells to ferroptosis via GCN2-dependent activation of the integrated stress response

TL;DR

Restricting certain amino acids makes lung cancer cells more vulnerable to a type of cell death called ferroptosis, potentially improving cancer treatment.

Contribution

The study reveals that amino acid restriction enhances ferroptosis sensitivity in lung cancer cells via GCN2 and the integrated stress response.

Findings

Reduced amino acids (excluding cysteine) increase BSO sensitivity in lung cancer cells.

GCN2 and the integrated stress response promote lipid peroxidation under glutathione depletion.

Amino acid restriction could be combined with ferroptosis-inducing agents for cancer therapy.

Abstract

Lung cancer cells are vulnerable to iron-dependent oxidation of phospholipids leading to ferroptosis, a process countered by glutathione peroxidase-4 that converts lipid hydroperoxides to lipid alcohols using glutathione as reducing agent. Since ferroptosis-inducing agents are in clinical development, identifying modifiers of ferroptosis susceptibility is warranted. Here, we investigate the impact of amino acids on susceptibility to buthionine sulfoximine (BSO), a glutamate-cysteine ligase inhibitor that blocks biosynthesis of glutathione. We found that reduced amounts of amino acids other than cysteine increased the sensitivity to BSO and other ferroptosis-inducing agents, in a panel of mouse and human lung cancer cells, without affecting glutathione production. Activation of the amino acid sensor protein GCN2 and the integrated stress response lowered the threshold for lipid peroxidation by promoting ATF4-dependent mitochondrial respiration and reactive oxygen species leakage from the electron transport chain under glutathione depletion. The finding provides new insights into lung cancer metabolism and raises the possibility of using amino acid restricted diets in combination with ferroptosis-inducing agents as cancer therapies.

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