The Major Facilitative Folate Transporters Solute Carrier 19A1 and Solute Carrier 46A1: Biology and Role in Antifolate Chemotherapy of Cancer

Abstract

This review summarizes the biology of the major facilitative membrane transporters, the reduced folate carrier (RFC) (Solute Carrier 19A1) and the proton-coupled folate transporter (PCFT) (Solute Carrier 46A1). Folates are essential vitamins, and folate deficiency contributes to a variety of health disorders. RFC is ubiquitously expressed and is the major folate transporter in mammalian cells and tissues. PCFT mediates the intestinal absorption of dietary folates and appears to be important for transport of folates into the central nervous system. Clinically relevant antifolates for cancer, such as methotrexate and pralatrexate, are transported by RFC, and loss of RFC transport is an important mechanism of methotrexate resistance in cancer cell lines and in patients. PCFT is expressed in human tumors, and is active at pH conditions associated with the tumor microenvironment. Pemetrexed is an excellent substrate for both RFC and PCFT. Novel tumor-targeted antifolates related to pemetrexed with selective membrane transport by PCFT over RFC are being developed. In recent years, there have been major advances in understanding the structural and functional properties and the regulation of RFC and PCFT. The molecular bases for methotrexate resistance associated with loss of RFC transport and for hereditary folate malabsorption, attributable to mutant PCFT, were determined. Future studies should continue to translate molecular insights from basic studies of RFC and PCFT biology into new therapeutic strategies for cancer and other diseases.

Structural determinants of human proton-coupled folate transporter oligomerization: role of GXXXG motifs and identification of oligomeric interfaces at transmembrane domains 3 and 6

“…hPCFT is detected at substantial levels in many human tumours [9,10] and shows appreciable activity at pH 6.5–6.8, depending on the substrate, although maximal activity occurs at pH 5–5.5 and transport is nominal above pH 7 [5,11]. The clinically relevant anti-folate Pmx is among the best substrates for hPCFT and at least part of its clinical efficacy is probably due to its membrane transport by hPCFT [3]. Most recently, novel cytotoxic folate analogues are being developed with transport specificities for PCFT over RFC for selectively targeting solid tumours [3,9, 12–17].…”

“…The clinically relevant anti-folate Pmx is among the best substrates for hPCFT and at least part of its clinical efficacy is probably due to its membrane transport by hPCFT [3]. Most recently, novel cytotoxic folate analogues are being developed with transport specificities for PCFT over RFC for selectively targeting solid tumours [3,9, 12–17]. …”

Substituted Cysteine Accessibility Reveals a Novel Transmembrane 2–3 Reentrant Loop and Functional Role for Transmembrane Domain 2 in the Human Proton-coupled Folate Transporter

“…Loss of hPCFT is associated with hereditary folate malabsorption syndrome, a rare autosomal recessive condition characterized by systemic folate deficiency and dramatically decreased folate levels in the central nervous system (3,(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Whereas hPCFT is also expressed in other normal tissues, the high levels of hPCFT in many solid tumors are of particular interest given their potential for tumor-targeting with novel hPCFT-selective cytotoxic antifolates (18,19).…”

Fluorine-Substituted Pyrrolo[2,3-d]Pyrimidine Analogues with Tumor Targeting via Cellular Uptake by Folate Receptor α and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine Nucleotide Biosynthesis

“…17 PCFT is also expressed in the liver and kidney. 3,4,18 PCFT is expressed in human tumors with particularly high levels in NSCLC, 19 EOC, 11 and malignant pleural mesothelioma. 20 PCFT functions in the cellular uptake of folates and antifolates at acidic pHs characterizing the microenvironments of many solid tumors.…”