Novel Approach to Destroy Cancer Cells: Exploiting Their Own Toxicity

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“Nature” Unveils a Novel Approach to Destroy Cancer Cells: Exploiting Their Own Toxicity

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“Nature” Unveils a Novel Approach to Destroy Cancer Cells: Exploiting Their Own Toxicity

A recent study published in “Nature” introduces a groundbreaking approach to cancer treatment that leverages the inherent vulnerability of cancer cells.

This method involves allowing cancer cells to continuously accumulate toxic metabolic byproducts, ultimately leading to their self-destruction.

By targeting cancer cells from within, this approach offers precise and efficient tumor elimination while sparing healthy cells.

The inspiration for this innovative research stems from the unique metabolic patterns of cancer cells. Some familiar aspects include high glucose consumption and imbalanced amino acid intake, such as the heavy reliance of many cancer cells on glutamine for survival and proliferation. Disrupting the supply of these metabolites from the outside can partially hinder cancer cell growth.

In addition to targeting the conventional enzymatic metabolic pathways, scientists also investigate the inner workings of cancer cells, particularly the enzymatic metabolic pathways. Similar to normal cells, cancer cells employ enzymes to synthesize the metabolites they require. Inhibiting a crucial enzyme can potentially reduce the building blocks essential for cell construction.

However, for conventional enzymatic metabolism, blocking one pathway may lead cancer cells to seek alternative routes to produce the necessary molecules. To address this challenge, researchers propose a “wastewater pool” model, similar to a scenario where wastewater is generated while simultaneously being processed in drainage pipes. In some enzymatic metabolic steps, cancer cells produce toxic intermediate products, which need another enzyme to convert them into non-toxic molecules. Inhibiting the second enzyme leads to the accumulation of toxic waste.

Using database screening, this new study identified a particular enzymatic metabolic pathway in which the upstream UGDH gene closely correlates with the downstream UXS1 enzyme. The primary role of UXS1 is to break down the intermediate product UDPGA generated by UGDH.

Specifically, UXS1 is a Golgi enzyme capable of converting UDP-glucuronic acid (UDPGA) into UDP-xylose. UXS1 not only reduces UDPGA levels but also forms a negative feedback loop, decreasing the expression of UGDH upstream.

Blocking UXS1 produces two distinct outcomes: the accumulation of UDPGA as one result and a reduction in the final product UDP-xylose as the other. The study aimed to differentiate which of these was lethal to cancer cells. Inhibition of the upstream UGDH gene expression, resulting in the loss of UDP-xylose downstream, did not alter cancer cell survival. This indicates that the loss of UDP-xylose is not the critical factor.

However, the accumulation of UDPGA led to different consequences. Knocking out the UXS1 enzyme caused cancer cells to gradually die. Analysis revealed significant damage to the Golgi apparatus within the cancer cells, with many Golgi-related genes undergoing modification. Simultaneously, some genes associated with DNA damage repair and cell cycle regulation showed disrupted expression. These changes ultimately led to the death of cancer cells, highlighting the severe toxicity of UDPGA accumulation.

The study emphasizes that many cancer cells express UGDH at higher levels compared to healthy cells, indicating that only cancer cells require the detoxifying function of UXS1. Therefore, by inhibiting the activity of UXS1 and targeting this weakness in cancer cells, there is hope for achieving precise cancer therapy.

References:

[1] Disruption of sugar nucleotide clearance is a therapeutic vulnerability of cancer cells. Nature (2023). DOI: https://doi.org/10.1038/s41586-023-06676-3

[2] Endogenous toxic metabolites and implications in cancer therapy. Oncogene (2020). DOI:10.1038/s41388-020-01395-9

“Nature” Unveils a Novel Approach to Destroy Cancer Cells: Exploiting Their Own Toxicity

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