Tumor cells have an increased demand for amino acids because of their rapid proliferation rate. In addition to their need in protein synthesis, several amino acids have other roles in supporting cancer growth. There are approximately two-dozen amino acid transporters in humans, and tumor cells must upregulate one or more of these transporters to satisfy their demand for amino acids. If the transporters that specifically serve this purpose in tumor cells are identified, they can be targeted for the development of a brand new class of anticancer drugs; the logical basis of such a strategy would be to starve the tumor cells of an important class of nutrients. To date, four amino acid transporters have been found to be expressed at high levels in cancer: SLC1A5, SLC7A5, SLC7A11, and SLC6A14. Their induction occurs in a cancer typespecific manner with a direct or indirect involvement of the oncogene c-Myc. Further, these transporters are functionally coupled, thus maximizing their ability to promote cancer growth and chemoresistance. Progress has been made in preclinical studies, exploiting these transporters as drug targets in cancer therapy. These transporters also show promise in development of new tumor-imaging probes and in tumor-specific delivery of appropriately designed chemotherapeutic agents. Cancer Res; 75(9);

The SLC (solute carrier)-type transporters (∼400 in number) in mammalian cells consist of 52 distinct gene families, grouped solely based on the amino acid sequence (primary structure) of the transporter proteins and not on their transport function. Among them are the transporters for amino acids. Fourteen of them, capable of transporting glutamine across the plasma membrane, are found in four families: SLC1, SLC6, SLC7, and SLC38. However, it is generally thought that the members of the SLC38 family are the principal transporters for glutamine. Some of the glutamine transporters are obligatory exchangers whereas some function as active transporters in one direction. While most glutamine transporters mediate the influx of the amino acid into cells, some actually mediate the efflux of the amino acid out of the cells. Glutamine transporters play important roles in a variety of tissues, including the liver, brain, kidney, and placenta, as clearly evident from the biological and biochemical phenotypes resulting from the deletion of specific glutamine transporters in mice. Owing to the obligatory role of glutamine in growth and proliferation of tumor cells, there is increasing attention on glutamine transporters in cancer biology as potential drug targets for cancer treatment. Selective blockers of certain glutamine transporters might be effective in preventing the entry of glutamine and other important amino acids into tumor cells, thus essentially starving these cells to death. This could represent the beginning of a new era in the discovery of novel anticancer drugs with a previously unexplored mode of action.

Short-chain fatty acids (SCFA; acetate, propionate, and butyrate) are generated in colon by bacterial fermentation of dietary fiber. Though diffusion in protonated form is a significant route, carrier-mediated mechanisms constitute the major route for the entry of SCFA in their anionic form into colonic epithelium. Several transport systems operate in cellular uptake of SCFA. MCT1 (SLC16A1) and MCT4 (SLC16A3) are H+-coupled and mediate electroneutral transport of SCFA (H+: SCFA stoichiometry; 1:1). MCT1 is expressed both in the apical membrane and basolateral membrane of colonic epithelium whereas MCT4 specifically in the basolateral membrane. SMCT1 (SLC5A8) and SMCT2 (SLC5A12) are Na+-coupled; SMCT1-mediated transport is electrogenic (Na+: SCFA stoichiometry; 2:1) whereas SMCT2-mediated transport is electroneutral (Na+: SCFA stoichiometry; 1:1). SMCT1 and SMCT2 are expressed exclusively in the apical membrane. An anion-exchange mechanism also operates in the apical membrane in which SCFA entry in anionic form is coupled to bicarbonate efflux; the molecular identity of this exchanger however remains unknown. All these transporters are subject to regulation, notably by their substrates themselves; this process involves cell-surface receptors with SCFA as signaling molecules. There are significant alterations in the expression of these transporters in ulcerative colitis and colon cancer. The tumor-associated changes occur via transcriptional regulation by p53 and HIF1α and by promoter methylation. As SCFA are obligatory for optimal colonic health, the transporters responsible for the entry and transcellular transfer of these bacterial products in colonic epithelium are critical determinants of colonic function under physiological conditions and in disease states.