Potential Cancer Therapy Target in Sugar Nucleotide Clearance

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New Study Reveals Potential Cancer Therapy Target in Sugar Nucleotide Clearance

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New Study Reveals Potential Cancer Therapy Target in Sugar Nucleotide Clearance

In today’s modern society, cancer rates are steadily increasing worldwide due to complex factors such as an aging population, worsening environmental pollution, and changing lifestyle habits. Notably, changes in metabolism play a crucial role in supporting cancer cell functions, including rapid proliferation and survival under various stressful conditions.

Recent research has uncovered the significance of specific metabolic activities in preventing the accumulation of toxic metabolites. Even more intriguing is the “kitchen sink” model, where detoxifying enzymes are only required in cells that produce toxic metabolites, much like a kitchen sink drain only needing to be open when the faucet is running.

On October 25, 2023, a research paper titled “Disruption of sugar nucleotide clearance is a therapeutic vulnerability of cancer cells” was published in the prestigious scientific journal Nature by the team led by Dr. Dohoon Kim from Harvard Medical School.

This study employed CRISPR-Cas9 gene screening of essential metabolic enzymes and discovered UXS1, a metabolic enzyme located in the Golgi apparatus. UXS1 is responsible for converting UDP-glucuronic acid (UDPGA) to UDP-xylose and is essential only in cells with high levels of the upstream enzyme UGDH.

Crucially, UGDH is highly expressed in various cancers, including lung adenocarcinoma, and its expression is further enhanced during chemotherapy resistance development. As a result, these cancer cells selectively rely on UXS1 for detoxifying UDPGA, revealing a potential therapeutic target in tumors with high UGDH expression.

During metabolism, cells inevitably produce harmful metabolites that require specialized detoxifying enzymes for elimination. In cancer cells, metabolic changes lead to the excessive accumulation of specific harmful metabolites, making detoxifying enzymes conditional essential genes for these tumor cells.

In this latest research, Dr. Dohoon Kim’s team used the DEPMAP cancer cell line dependency database to identify essential metabolic enzymes in certain cancer cell lines. Using the kitchen sink model, they found that the Golgi enzyme UXS1 is likely a conditional essential enzyme in specific types of tumors.

To confirm this, the research team conducted CRISPR-Cas9 gene knockouts of UXS1 in 19 different cancer cell lines derived from various tissues. These cell lines exhibited varying levels of UGDH mRNA expression, but the results showed that the absence of UXS1 was detrimental only to cell lines with high UGDH expression.

UXS1 is essential for cell survival and is associated with cell line-specific expression of the upstream enzyme UGDH

UGDH is an NAD+-dependent enzyme that catalyzes the double oxidation of UDP-glucose (UDP-Glc) to produce UDP-glucuronic acid (UDPGA). Notably, UXS1 is a downstream enzyme of UGDH, capable of converting UDPGA to UDP-xylose, preventing the excessive accumulation of UDPGA generated by UGDH.

Subsequently, the team measured UDPGA levels in UXS1-knockout cell lines using liquid chromatography-mass spectrometry (LC-MS). As expected, UXS1 depletion led to a time-dependent overaccumulation of UDPGA, approximately 70 times higher than normal levels. Moreover, UDPGA accumulation resulted in a decrease in UDP-xylose, leading to the loss of xylose modifications within the cells.

UXS1 knockdown leads to excessive accumulation of UDPGA

Further investigations revealed that excessive UDPGA disrupted the morphology and function of the Golgi apparatus, hindering the transport of surface receptors like epidermal growth factor receptor (EGFR) to the cell membrane and reducing cellular signaling capacity. Additionally, the reduced UDP-xylose led to enhanced UGDH activity, exacerbating UDPGA overaccumulation.

In summary, UXS1 enzyme not only clears UDPGA through metabolic reactions but also negatively regulates UGDH enzyme, reducing UDPGA production.

Accumulation of UDPGA can lead to Golgi dysfunction, resulting in inactivation of the EGFR signaling pathway

Moreover, the research team demonstrated the significance of the UXS1-UGDH axis in cancer therapy since many types of cancer cells exhibit high UGDH levels compared to healthy cells, and this feature is further intensified during chemotherapy resistance development. Dr. Dohoon Kim, the lead author of the paper, suggested that UXS1 might be a potential new target for treating UGDH-high expressing cancers.

UXS1 is a cancer-selective therapeutic target as UGDH expression is elevated in cancer subpopulations and chemoresistant cancer cells

Furthermore, this research unveiled unexpected connections between sugar nucleotide metabolism pathways and the regulation of signal transduction processes. Therefore, elevated UDPGA can not only directly “poison” cancer cells but also silence their response to extracellular signals, enhancing the effectiveness of cancer treatment. This concept may have wide-ranging applications in cell biology and extend beyond cancer therapy into various aspects of health and well-being.

Paper Link: [Read more](https://www.nature.com/articles/s41586-023-06676-3)

New Study Reveals Potential Cancer Therapy Target in Sugar Nucleotide Clearance

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