How a Vitamin Transporter Can Be Used As a Cancer Therapeutic
Last Week in Medicine
Before I explain these two hard studies, there are a few things we need to learn. The first is signaling molecules called CDNs. CDNs are potent inducers of the innate immune response. They show their functions by activating the genes named STING (Stimulator of InterferoN Genes). Because these genes are inside the cell, CDNs must cross the cell membrane and to perform this crossing, they use the SLC19A1 transporter. Finally, the transporter named SLC19A1 has another function, regulating intracellular concentrations of folates (Vitamin B9). Using this function of SLC19A1, Methotrexate, a chemotherapy agent, acts as an antifolate molecule and suppresses the immune response.
We can see that the SLC19A1 has many significant functions. However, we do not know how SLC19A1 recognizes these molecules and allows them to pass through the cell membrane. Two new studies published in the journal Nature shed light on this issue.
First of all, Zhang and Wright et al. present how methotrexate (MTX) binds to SLC19A1. Using cryo-electron microscopy, they show that MTX bind to central part of SLC19A1. This is important because CDNs also use the same transporter but binds to another site near the cytoplasmic side of the membrane.
SLC19A1 is not just specific to these molecules. It is a transporter that also functions for many anions, organic and inorganic molecules. Therefore, to design better anticancer drugs, it is valuable to learn spesific binding sites of it.
I said that CDNs are potent inducers of immune response. And they do this by activating STING. In this way, a signal cascade occurs further anticancer response develops. Using this mechanism, anticancer drugs called STING agonists have been developed. However, it was observed that these drugs showed only modest therapeutic activity. Zhang and Wright et al. reveals how CDNs and folate are recognized by SLC19A1. Acknowleding these discoveries, more effective STING agonists can be developed.
Zhang and Wright et al. identify how a vitamin transporter interacts with antifolate agents used in cancer therapy, how signal molecules that activate the immune system are transported across the cell membrane, by showing specific binding sites. Thanks to their work, they are paving the way for a new generation of cancer therapeutics targeting the SLC carrier family.
