Impact of the Reduced Folate Carrier on the Accumulation of Active Thiamin Metabolites in Murine Leukemia Cells*

  title={Impact of the Reduced Folate Carrier on the Accumulation of Active Thiamin Metabolites in Murine Leukemia Cells*},
  author={Rongbao Zhao and Feng Gao and Yanhua Wang and George A Diaz and Bruce D. Gelb and I. David Goldman},
  journal={The Journal of Biological Chemistry},
  pages={1114 - 1118}
The thiamin transporter encoded bySLC19A2 and the reduced folate carrier (RFC1) share 40% homology at the protein level, but the thiamin transporter does not mediate transport of folates. By using murine leukemia cell lines that express no, normal, or high levels of RFC1, we demonstrate that RFC1 does not mediate thiamin influx. However, high level RFC1 expression substantially reduced accumulation of the active thiamin coenzyme, thiamin pyrophosphate (TPP). This decreased level of TPP… 

Figures and Tables from this paper

Reduced folate carrier transports thiamine monophosphate: an alternative route for thiamine delivery into mammalian cells.
The data suggest that RFC1 may be one of the alternative transport routes available for TMP in some tissues when THTR-1 is mutated in the autosomal recessive disorder thiamine-responsive megaloblastic anemia.
Loss of Multidrug Resistance Protein 1 Expression and Folate Efflux Activity Results in a Highly Concentrative Folate Transport in Human Leukemia Cells*
It is established for the first time that MRP1 is the primary folate efflux route in CEM leukemia cells and that the loss of folates and folic acid efflux activity is an efficient means of markedly augmenting cellular folate pools.
Other mechanisms to explain the role of reduced folate carrier in cancer
High levels of RFC are essential for a correct uptake of methotrexate but also for efflux of intracellular thiamine and maybe for the transport of other anticancer agents.
Biological Role, Properties, and Therapeutic Applications of the Reduced Folate Carrier (RFC-SLC19A1) and the Proton-Coupled Folate Transporter (PCFT-SLC46A1)
This review focuses on the facilitative pathways of (anti)folate transport, including RFC and PCFT in relation to their molecular properties, and their physiological and pharmacological roles.
The Mechanism of Carrier-Mediated Transport of Folates in BeWo Cells: The Involvement of Heme Carrier Protein 1 in Placental Folate Transport
It is concluded that pH-dependent folate uptake in BeWo cells is mediated by at least two carriers, including RFC and HCP1, both of which transport folates in the model cell line for the placenta.
The Major Facilitative Folate Transporters Solute Carrier 19A1 and Solute Carrier 46A1: Biology and Role in Antifolate Chemotherapy of Cancer
The molecular bases for methotrexate resistance associated with loss of RFC transport and for hereditary folate mal absorption, attributable to mutant PCFT, were determined and 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.
The Reduced Folate Carrier Gene Is a Novel Selectable Marker for Recombinant Protein Overexpression
A novel RFC- based metabolic selection system for the efficient overexpression of recombinant proteins is established and the possible implications to subcellular transporter localization and restoration of MTX sensitivity in drug-resistant tumors by RFC-based gene therapy are discussed.
A high-affinity and specific carrier-mediated mechanism for uptake of thiamine pyrophosphate by human colonic epithelial cells.
  • S. Nabokina, H. Said
  • Biology
    American journal of physiology. Gastrointestinal and liver physiology
  • 2012
The findings suggest the involvement of a carrier-mediated mechanism for TPP uptake by colonic NCM460 cells, which was further confirmed by results from studies of native human colonic apical membrane vesicles, and suggest that the bacterially synthesized TPP in the large intestine is bioavailable and may contribute to overall body homeostasis of vitamin B1 and to the cellular nutrition of the local colonocytes.


Sensitivity to 5,10-dideazatetrahydrofolate is fully conserved in a murine leukemia cell line highly resistant to methotrexate due to impaired transport mediated by the reduced folate carrier.
Resistance to one antifolate, in this case MTX, because of a loss of RFC1 transport activity need not exclude the subsequent utility of another antIFolate that uses the same carrier.
A Reduced Folate Carrier Mutation Produces Substrate-dependent Alterations in Carrier Mobility in Murine Leukemia Cells and Methotrexate Resistance with Conservation of Growth in 5-Formyltetrahydrofolate*
The mutated RFC1 cDNA represents the first reported RFC1 mutation that confers resistance to MTX due to a markedly impaired influx with relative conservation of reduced folate transport, allowing tumor cells to meet their folate requirement with 5-CH3THF, the predominant blood folate.
Evidence for a functional defect in the translocation of the methotrexate transport carrier in a methotrexate-resistant murine L1210 leukemia cell line.
In two partial revertants with increased MTX sensitivity isolated from the second-step resistant lines, MTX influx was increased but surface membrane-binding sites were unchanged suggesting that recovery of transport was due to normalization of carrier function rather than an increase in the number of carriers.
Cloning of the Human Thiamine Transporter, a Member of the Folate Transporter Family*
A cDNA from human placenta is isolated, which, when expressed heterologously in mammalian cells, mediates the transport of the water-soluble vitamin thiamine and is most likely the gene defective in the metabolic disorder,Thiamine-responsive megaloblastic anemia.
Pattern of mutations that results in loss of reduced folate carrier function under antifolate selective pressure augmented by chemical mutagenesis.
Data suggest that several transmembrane domains, rather than the amino- and carboxyl-termini, and the large intracellular loop between the sixth and seventh transmemBRane domains play key roles as sites for RFC1 inactivation because of single point mutations.
The gene mutated in thiamine-responsive anaemia with diabetes and deafness (TRMA) encodes a functional thiamine transporter
Evidence is presented that the gene SLC19A2 (for solute carrier family 19 (thiamine transporter), member 2) encodes the first known mammalian thiamineporter-1 (THTR-1), which is designed to correct anaemia and improve diabetes in people with TRMA.