Researchers from the Giulio Superti-Furga Lab at CeMM, the Austrian Academy of Sciences’ Research Center for Molecular Medicine, have developed a new technique for identifying specific inhibitors of a lactate transporter linked to cancer and other diseases.
The compound discovered in the assay system could pave the way for new cancer treatments. The findings have now been published in Cell Chemical Biology.
Transporter proteins, which are primarily found in the cell membrane and regulate the supply and removal of nutrients like amino acids, sugars, and nucleotides for a cell, include their largest class, the solute carrier (SLC) family. They are important participants in cell metabolism and play a crucial part in both health and disease.
Although they play a crucial physiological role and are attractive therapeutic targets, the majority of SLCs have not yet received adequate pharmacological research.
This is exactly what numerous researchers in the research team of Giulio Superti-Furga, Scientific Director at the CeMM, the Austrian Academy of Sciences Research Center for Molecular Medicine, and a Professor at the Medical University of Vienna, are working on.
The lactate transporters SLC16A1 and SLC16A3, which are linked to a number of cancers and other diseases, can now be targeted using a new technique.
Lactate, a glycolysis byproduct, is particularly known as a metabolic waste product, but it is also used as an energy source. In fact, it has been demonstrated that highly glycolytic cells produce lactate, which is then used as an energy source by neighboring cells in many tissues.
This has been observed in the skeletal muscle, brain, testes, and tumor microenvironment (TME), among other places. Lactate is primarily transported across the membrane by SLC16 family members. Studies have found that the SLC16A1 (MCT1) and SLC16A3 (MCT4) genes play a critical role in the transport of lactate.
We know for more than a century that tumor cells tend to be highly glycolytic, and that the concentration of lactate can reach extreme levels inside tumors. But it is only relatively recently that we are starting to understand the consequences of this. For example, the high lactate levels are contributing to the suppression of immune cells inside the tumors, or to the development of resistances to treatment.”
Giulio Superti-Furga, CeMM
Giulio Superti-Furga adds, “Lactate transporters have a key role in this, especially SLC16A1 and SLC16A3, known as the major lactate importer and the major lactate exporter. Both transporters are considered promising drug targets.”
One of the major obstacles for the development of novel drugs that target SLCs are the frequent functional redundancies among several transporters that are present in cells. This makes it very difficult to isolate the impact of a potential drug candidate on a single transporter and hence determine the selectivity. In one of our previous projects, we found a synthetic lethality between SLC16A1 and SLC16A3 present in several cell models.”
Vojtech Dvorak, Study First Author and PhD Student, CeMM
“That is, the cell normally has both transporters, and when one of them is either inhibited by the drug, or the gene for one of them is lost, the other transporter can compensate. However, when say, the SLC16A1 gene is lost, the cell then actually depends on SLC16A3 for its survival (and vice versa). We realized that we could create several cell lines that are dependent on either of the distinct lactate transporters and use them to search for highly selective drugs,” explains Vojtech Dvorak.
The researchers describe the development of the assay system, known as the Paralog-dependent isogenic cell assay, or PARADISO for short, and its application to the development of a highly selective chemical probe targeting SLC16A3, known as slCeMM1.
The lack of specific cell-based assays is a problem for many promising drug targets, not only for SLCs. The logic of the PARADISO assay system should be in principle widely applicable and help to find new therapeutic targets.”
Giulio Superti-Furga, CeMM
Dvorak, V., et al. (2023) Paralog-dependent isogenic cell assay cascade generates highly selective SLC16A3 inhibitors. Cell Chemical Biology. doi.org/10.1016/j.chembiol.2023.06.029.