MassIVE MSV000088066

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The vulnerability of actin cytoskeleton to disulfide stress dictates high SLC7A11-driven cell death upon glucose deprivation

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Description

Solute carrier family 7 member 11 (SLC7A11; also known as xCT) is a cystine transporter frequently overexpressed in cancers. Cancer cells with high expression of SLC7A11 (SLC7A11high) are resistant to ferroptosis but exquisitely sensitive to glucose deprivation-induced cell death, although the underlying mechanism of the latter cell death remains poorly understood. Here we show that We found that glucose deprivation induced a novel type of cell death in SLC7A11high cancer cells that was different from apoptosis or ferroptosis. And the bioorthogonal chemical proteomics analysis revealed that a large amount of actin cytoskeleton proteins were shown with significantly dysregulated disulfides induced by glucose starvation in SLC7A11high cancer cells. In mechanism, SLC7A11high mediated cystine uptake and subsequent reduction to cysteine forced disulfide stress on actin cytoskeleton upon glucose deprivation through draining intracellular reduced nicotinamide adenine dinucleotide phosphate (NADPH) pool, which was independent of generating reactive oxygen species (ROS). The disulfide stress on the actin cytoskeleton induced rapidly contracted actin filaments and detached from the plasma membrane, which incurred cell death. In the end, using whole-genome CRISPR/Cas9 knock-out screening we identified NCKAP1 as a downstream factor of SLC7A11 to promoting cell death upon glucose deprivation by inhibiting branched actin filaments. [doi:10.25345/C58V78]

Keywords: SLC7A11 ; actin cytoskeleton ; disulfide

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Principal Investigators:
(in alphabetical order) 		Litong Nie, MD Anderson Cancer Center, United States
Submitting User: Litong
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