International Business Department           Liu Bojia           Feburary 23, 2023

  For fast-growing cancer cells, finding sufficient energy is a top priority, as their cell proliferation and various cellular functions are dependent on energy support. Previous studies have found that many tumour types are highly dependent on mitochondrial oxidative metabolism to sustain aggressive growth and metastasis. This is not difficult to understand; after all, mitochondria are the energy factories of the cell, and it is logical that cancer cells would elevate the workload of mitochondria.

  In acute myeloid leukaemia (AML), for example, these cancers are highly aggressive and expand rapidly, which is inseparable from their enhanced mitochondrial function. In response to this rapid proliferation, scientists also believe that the mitochondria of AML tumours may be a viable therapeutic target.

  According to new research recently published in Cell Metabolism, scientists from the University of Texas at Austin have found that AML cells accelerate mitochondrial function by expanding "fuel" delivery channels to provide more support for tumour growth, and that by rationally lowering the levels of specific proteins, the researchers were able to reduce the amount of "fuel" available to cancer cells. By reducing the levels of specific proteins, researchers can reduce the supply of mitochondrial "fuel" to cancer cells and inhibit tumour growth.

  According to the paper, rapidly proliferating cells have a high demand for oxidised nicotinamide adenine dinucleotide ( ^NAD+ ), and during oxidative metabolism, the mitochondria act as a hub for ^NAD+. Cancer cells often try to upregulate the ^NAD+ synthesis pathway to accelerate proliferation, and this is no exception for AML tumours, where many studies have found thatthe higher the ^NAD+level, the more resistant AML is to chemotherapy.

  However, in actual treatment, we cannot directly remove ^NAD+ from an individual because normal cellular function also requires ^NAD+, which requires us to find and control the specific ^NAD+ regulation in cancer cells. Instead, the researchers found that the transporter protein SLC25A51 takes on exactly the job of regulating ^NAD+, and it will selectively transport ^NAD+ from the cytoplasm to the interior of the mitochondria, thereby boosting the level of ATP production.

  The researchers obtained tumour samples from a number of AML patients and examined the levels of SLC25A51 in the cells. AML tumour cells had significantly elevated levels of SLC25A51 compared to normal levels, and patients with higher levels of SLC25A51 tended to have poorer treatment outcomes.

  They attempted to knock down SLC25A51 in several types of leukaemia tumours and saw a reduction in ^NAD+ levels within the mitochondria of these cells, while tumour cell proliferation was significantly inhibited.

  In addition to being feasible in cellular experiments, this strategy was equally effective in tumour-bearing mice. Mice undergoing AML tumour transplantation at the same time with reduced expression of SLC25A51 were observed to have a reduced tumour burden after approximately 3 weeks, and fewer metastatic cancer cells appeared in their spleens compared to controls , with prolonged survival of the mice. This change did not affect, for example, other processes of glycolysis.

  Meanwhile, inhibition of SLC25A51 could be combined with conventional chemotherapy to further enhance survival in the mice, which the researchers believe is because a reduction in SLC25A51 causes cancer cells to become more sensitive to chemotherapeutic drugs.

  The authors note that in the future we need to look for a molecule that can safely reduce SLC25A51, which would need to reduce SLC25A51 to basal levels, but would not affect normal expression. This would specifically inhibit cancer cells that overexpress SLC25A51 without causing side effects on healthy cells.