International Business Department           Liu Bojia           November 01, 2023

  A recent study in the journal Nature has discovered a novel method of cancer eradication, which essentially exploits the weakness of cancer cells to produce their own toxic metabolites, allowing them to accumulate toxic metabolites and ultimately be "poisoned" by themselves. This method of breaking down the cancer cells from within can precisely and efficiently eliminate the tumour, sparing unrelated healthy cells.

  The new study was inspired by the specific metabolic patterns of cancer cells. Aspects we may be familiar with include high levels of glucose consumption, or dysregulated amino acid uptake, such as the particular dependence of many cancer cells on glutamine for survival and proliferation. Blocking the supply of these metabolites directly from the outside can inhibit cancer cell growth to some extent.

  In addition to this, studies also look at the internal aspects of cancer cells, such as enzyme metabolic pathways. Like normal cells, cancer cells use enzymes to synthesise the metabolites they need, and inhibiting a key enzyme may reduce the number of modular molecules needed for cellular construction.

  However, for conventional enzyme metabolism, blocking the enzymes of a particular pathway, cancer cells may have another alternative route to produce the desired product. Scientists also need an alternative route, and one study proposes a "wastewater pond" model, which is similar to the scenario of producing wastewater and treating it as it goes down the drain, where the cancer cell also produces toxic intermediates at certain steps of enzyme metabolism, and then needs another enzyme to process them into non-toxic molecules, and blocking the second enzyme allows the waste to accumulate.

  With the help of database screening, the new study found a special enzyme metabolic pathway, in which the UGDH gene located upstream is closely related to the expression of the UXS1 enzyme downstream, and the UXS1 enzyme's main role is to break down the intermediate product UDPGA produced by UGDH.

  Specifically, UXS1 is a class of Golgi enzymes that converts the sugar nucleotide UDP-glucuronide (UDPGA) to UDP-xylose.UXS1 not only reduces the level of UDPGA, but also creates a negative feedback that reduces upstream UGDH expression.

  Of course, blocking UXS1 produces two results, one is the accumulation of the intermediate product UDPGA, and the other is the reduction of the end product UDP-xylose, which one is fatal to cancer cells?

  To make the distinction, the authors attempted to directly inhibit the expression of the upstream gene UGDH, which again resulted in the loss of UDP-xylulose downstream of the pathway, but there was no change in the survival of the cancer cells. This suggests that the loss of UDP-xylulose is not critical.

  The accumulation of UDPGA caused a different result, after the knockdown of UXS1 enzyme, the cancer cells started to die gradually, while the analysis showed that the Golgi apparatus of the cancer cells was heavily damaged, and many Golgi-related genes were modified, while some genes related to the repair of DNA damage and the cell cycle were disorganised in their expression. These changes ultimately led to the death of the cancer cells, which means that the accumulation of UDPGA is severely toxic.

  The study points out that many cancer cells will highly express UGDH relative to healthy cells, which means that only cancer cells require the detoxifying effects of UXS1. Therefore by inhibiting the activity of UXS1 and capturing this weakness of cancer cells, it is expected that precision anti-cancer can be achieved.