Amino Acid Transporters in Cancer and Their Relevance to “Glutamine Addiction”: Novel Targets for the Design of a New Class of Anticancer Drugs

Abstract

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);

Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

“…Timeline of key discoveries in mammalian glutamine metabolism and cancer α-KG, α-ketoglutarate; GLUD, glutamate dehydrogenase. Glutamine enters the mammalian cell through transporters such as SLC1A5 (also known as ASCT2) 15 . Glutamine itself can contribute to nucleotide biosynthesis and uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) synthesis for support of protein folding and trafficking 210 , or is converted to glutamate by glutaminase (GLS or GLS2) 28 .…”

From Carbon-11-Labeled Amino Acids to Peptides in Positron Emission Tomography: the Synthesis and Clinical Application

“…Interestingly, this tracer utilizes a different mechanism of action in tumors and its uptake is complementing glucose metabolism. Cells are able to employ alternative energy sources, compared to all other available AAs tracer so far, which are mostly dependent on elevated levels of AAtransporters on the cell membrane [125]. All this suggest there is still a great interest in glutamine or its derivatives as PET tracer.…”

The potential of inhibiting glutamine uptake as a therapeutic target for multiple myeloma

“…Several transport systems are devoted to Gln transport in mammalian cells [5]. These transporters widely differ for dependence on ion gradients, affinity, and nature of the transport process.…”