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Disruption of sugar nucleotide clearance is a therapeutic vulnerability of cancer cells
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Disruption of sugar nucleotide clearance is a therapeutic vulnerability of cancer cells
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Journal Article
Disruption of sugar nucleotide clearance is a therapeutic vulnerability of cancer cells
2023
Overview
Identifying metabolic steps that are specifically required for the survival of cancer cells but are dispensable in normal cells remains a challenge
1
. Here we report a therapeutic vulnerability in a sugar nucleotide biosynthetic pathway that can be exploited in cancer cells with only a limited impact on normal cells. A systematic examination of conditionally essential metabolic enzymes revealed that UXS1, a Golgi enzyme that converts one sugar nucleotide (UDP-glucuronic acid, UDPGA) to another (UDP-xylose), is essential only in cells that express high levels of the enzyme immediately upstream of it, UGDH. This conditional relationship exists because UXS1 is required to prevent excess accumulation of UDPGA, which is produced by UGDH. UXS1 not only clears away UDPGA but also limits its production through negative feedback on UGDH. Excess UDPGA disrupts Golgi morphology and function, which impedes the trafficking of surface receptors such as EGFR to the plasma membrane and diminishes the signalling capacity of cells. UGDH expression is elevated in several cancers, including lung adenocarcinoma, and is further enhanced during chemoresistant selection. As a result, these cancer cells are selectively dependent on UXS1 for UDPGA detoxification, revealing a potential weakness in tumours with high levels of UGDH.
An enzyme called UXS1 that converts one sugar nucleotide to another is needed more in some cancer cells than in normal cells, providing a potential weakness that can be exploited therapeutically.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
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/ 42
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/ 64/60
/ 82/29
/ Ablation
/ Acids
/ Cancer
/ Cells
/ CRISPR
/ Enzymes
/ Glucose
/ Humanities and Social Sciences
/ Humans
/ Science
/ Sugar
/ Toxicity
/ Uridine Diphosphate Glucuronic Acid - biosynthesis
/ Uridine Diphosphate Glucuronic Acid - metabolism
