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Biological Role, Properties, and Therapeutic Applications of the Reduced Folate Carrier (RFC-SLC19A1) and the Proton-Coupled Folate Transporter (PCFT-SLC46A1)

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Targeted Drug Strategies for Cancer and Inflammation

Abstract

The mechanisms by which folates are transported across cell membranes have been an area of research interest for nearly five decades. Major transport systems include the facilitative carriers, the reduced folate carrier (RFC) and the proton-coupled folate transporter (PCFT), and the high affinity folate receptors (FRs) α and β which transport folates by endocytosis. RFC is the major transport system in mammalian cells and tissues for folate cofactors and clinically relevant antifolate drugs including methotrexate, raltitrexed, pemetrexed, and pralatrexate. PCFT was identified in 2006 as the mechanism by which folates are transported across the apical brush border of the proximal small intestine. Whereas both PCFT and RFC are widely expressed in tumors, PCFT differs from RFC in its acidic pH optimum which favors transport at the low pH commonly found in the hypoxic microenvironment of solid tumors. Reflecting tumor-specific patterns of expression and/or function, recent studies have focused on the identification of folate-targeted therapeutics with selective transport by PCFT and FRs over RFC. The goal is to circumvent RFC and the potentially toxic consequences of drug transport by RFC in normal tissues. RFC in tumor cells can also influence the pharmacologic activity of PCFT and FR-selective agents by transporting physiological folates which compete for polyglutamylation and binding to intracellular targets. This review focuses on the facilitative pathways of (anti)folate transport, including RFC (SLC19A1) and PCFT (SLC46A1) in relation to their molecular properties, and their physiological and pharmacological roles.

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Abbreviations

AICAR:

5-Amino-4-imidazolecarboxamide ribonucleotide

AICARTase:

5-Amino-4-imidazolecarboxamide ribonucleotide formyltransferase

ALL:

Acute lymphoblastic leukemia

BCRP:

Breast-cancer resistant protein

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

5-FormylTHF:

5-Formyltetrahydrofolate

FR:

Folate receptor

GARFTase:

Glycinamide ribonucleotide formyltransferase

GlpT:

Glycerol phosphate/inorganic phosphate antiporter

HFM:

Hereditary folate malabsorption

LacY:

Lactose/proton symporter

5-MethylTHF:

5-Methyltetrahydrofolate

MFS:

Major facilitator superfamily

MRP:

Multidrug resistance-associated protein

mTOR:

Mammalian target of rapamycin

MTX:

Methotrexate

OAT:

Organic anion transporters

PCFT:

Proton-coupled folate transporter

RFC:

Reduced folate carrier

RTX:

Raltitrexed

SCAM:

Substituted cysteine accessibility methods

THF:

Tetrahydrofolate

TMD:

Transmembrane domain

UTR:

Untranslated region

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Acknowledgment

This work was supported in part by grants from the National Institutes of Health, National Cancer Institute, CA53535 (LHM), CA152316 (LHM), and CA82621 (IDG).

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Authors and Affiliations

  1. Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, 110 East Warren Avenue, Detroit, MI, 48201, USA

    Larry H. Matherly

  2. Department of Oncology, Wayne State University School of Medicine, Detroit, MI, 48201, USA

    Larry H. Matherly

  3. Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, 48201, USA

    Larry H. Matherly

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  1. Larry H. Matherly
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  2. Ndeye Diop-Bove
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  3. I. David Goldman
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Correspondence to Larry H. Matherly .

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    Christopher P. Leamon

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Matherly, L.H., Diop-Bove, N., Goldman, I.D. (2011). Biological Role, Properties, and Therapeutic Applications of the Reduced Folate Carrier (RFC-SLC19A1) and the Proton-Coupled Folate Transporter (PCFT-SLC46A1). In: Jackman, A., Leamon, C. (eds) Targeted Drug Strategies for Cancer and Inflammation. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-8417-3_1

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