Nutrient transporters: the Achilles' heel of anabolism

Abstract

Highly proliferative cells, including cancer cells, require a constant supply of molecular building blocks to support their growth. To acquire substrates such as glucose and amino acids from the extracellular space, dividing cells rely on transporter proteins in the plasma membrane. Numerous studies link transcriptional and post-translational control of nutrient transporter expression with proliferation, highlighting the importance of nutrient transporters in both physiologic and pathologic growth. Here we review recent work that spotlights the crucial role of nutrient transporters in cell growth and proliferation, discuss post-translational mechanisms for coordinating expression of different transporters, and consider the therapeutic potential of targeting these proteins in cancer and other diseases characterized by inappropriate cell division.

Figure 1. Nutrient transporters involved in proliferation

Transporters clearly linked to cell growth are shown. Glucose imported through SGLTs or GLUTs feeds into glycolysis to promote biosynthesis and generate ATP. Net amino acid import through transporters including SNAT1, SNAT2, and ATB^0,+ supplies glutamine that enters the TCA cycle and is used for glutathione synthesis. Additionally, these transporters supply glutamine and other amino acids that serve as exchange substrates for transporters such as ASCT2, 4F2hc/LAT1, and 4F2hc/xCT. EAA import through LAT1 activates pro-growth pathways through mTORC1, while cystine transported through xCT helps protect against oxidative stress by supporting glutathione (GSH) production. While glutamine is the indicated LAT1 exchange substrate, other amino acids may take its place. See Table 1 for all preferred transporter substrates. In all cases, co-transported ions have been omitted for simplicity.