Genetic and nutritional deficiencies in folate metabolism influence tumorigenicity in Apcmin/+ mice

Lawrance, Andrea K.; Deng, Liyuan; Brody, Lawrence C.; Finnell, Richard H.; Shane, Barry; Rozen, Rima

doi:10.1016/j.jnutbio.2006.06.001

Cited by 18 publications

(21 citation statements)

References 37 publications

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“…Moreover, low dietary folate did not appear to significantly impact tumorigenesis in this mouse model [66].…”

Section: Rfc and Cancer Etiologymentioning

confidence: 66%

“…However, in another report [66], using the Apc min/+ mouse model of colon cancer, Apc min/+ mice with a heterozygous knockout of the RFC gene (RFC +/− ) developed fewer adenomas and carried a lower tumor load compared to RFC +/+ Apc min/+ mice. Moreover, low dietary folate did not appear to significantly impact tumorigenesis in this mouse model [66].…”

Section: Rfc and Cancer Etiologymentioning

confidence: 99%

See 1 more Smart Citation

Human reduced folate carrier: translation of basic biology to cancer etiology and therapy

Matherly

Hou

Deng

2007

Cancer Metastasis Rev

238

342

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This review attempts to provide a comprehensive overview of the biology of the physiologically and pharmacologically important transport system termed the "reduced folate carrier" (RFC). The ubiquitously expressed RFC has unequivocally established itself as the major transport system in mammalian cells and tissues for a group of compounds including folate cofactors and classical antifolate therapeutics. Loss of RFC expression or function may have potentially profound pathophysiologic consequences including cancer. For chemotherapeutic antifolates used for cancer such as methotrexate or pemetrexed, synthesis of mutant RFCs or loss of RFC transcripts and proteins results in antifolate resistance due to incomplete inhibition of cellular enzyme targets and insufficient substrate for polyglutamate synthesis. Since RFC was first cloned in 1994, tremendous advances have been made in understanding the complex transcriptional and posttranscriptional regulation of RFC, in identifying structurally and functionally important domains and amino acids in the RFC molecule as a prelude to establishing the mechanism of transport, and in characterizing the molecular defects in RFC associated with loss of transport in antifolate resistant cell line models. Many of the insights gained from laboratory models of RFC portend opportunities for modulating carrier expression in drug resistant tumors, and for designing a new generation of agents with improved transport by RFC or substantially enhanced transport by other folate transporters over RFC. Many of the advances in the basic biology of RFC in cell line models are now being directly applied to human cancers in the clinical setting, most notably pediatric acute lymphoblastic leukemia and osteogenic sarcoma.

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“…Moreover, low dietary folate did not appear to significantly impact tumorigenesis in this mouse model [66].…”

Section: Rfc and Cancer Etiologymentioning

confidence: 66%

Section: Rfc and Cancer Etiologymentioning

confidence: 99%

Human reduced folate carrier: translation of basic biology to cancer etiology and therapy

Matherly

Hou

Deng

2007

Cancer Metastasis Rev

238

342

View full text Add to dashboard Cite

show abstract

“…A summary of the 13 studies [39,[57][58][59][60][61][62][63][64][65][66][67][68] is presented in Table 1, with highlights of the significant outcomes from each. Fig.…”

Section: Studies Meeting the Inclusion Criteriamentioning

confidence: 99%

“…A study by Lawrance et al used a genetically modified Apc Min/+ mouse, which was genetically deficient in cellular folate uptake or folate metabolism, to study the effects of folate deficiency on tumorigenesis [63]. To generate these double mutant strains the Apc Min/+ mice were crossed with reduced folate carrier 1 (Rfc1) knockout mice or with methionine synthase (MTR) knockout mice.…”

Section: Studies Which Investigated Folate Deficiency Onlymentioning

confidence: 99%

The influence of folate and methionine on intestinal tumour development in the ApcMin/+ mouse model

Teh

Symonds

Bull

et al. 2012

Mutation Research/Reviews in Mutation Research

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“…For instance, APC min/+ mice in which one copy of RFC was inactivated developed significantly fewer intestinal adenomas than mice with two functional RFC alleles (Lawrance et al, 2007). Conversely, ablation of one RFC allele in mice decreased plasma Sadenosyl methionine/S-adenosyl homocysteine, increased colonocyte proliferation, increased transcripts for colon cancer-related genes (e.g., Cdh1, Cdx1, Igf2, and Ptgs2) regulated by methylation, and increased susceptibility to carcinogen (azoxymethane), as reflected in the numbers of aberrant crypt foci in colon (Ma et al, 2005).…”

Section: Folate Transport In Tissue Folate Homeostasis and Physimentioning

confidence: 99%

Chapter 5 Structure and Function of the Reduced Folate Carrier

Matherly

Hou

2008

Vitamins &Amp; Hormones

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Folates are essential for life and folate deficiency contributes to a host of health problems including cardiovascular disease, fetal abnormalities, neurologic disorders, and cancer. Antifolates, represented by methotrexate, continue to occupy a unique niche among the modern day pharmacopoeia for cancer along with other pathologic conditions. This review focuses on the biology of the membrane transport system termed the "reduced folate carrier" or RFC with a particular emphasis on RFC structure and function. The ubiquitously expressed RFC is the major transporter for folates in mammalian cells and tissues. Loss of RFC expression or function portends potentially profound physiologic or developmental consequences. For chemotherapeutic antifolates used for cancer, loss of RFC expression or synthesis of mutant RFC protein with impaired function results in antifolate resistance due to incomplete inhibition of cellular enzyme targets and low levels of substrate for polyglutamate synthesis. The functional properties for RFC were first documented nearly 40 years ago in murine leukemia cells. Since 1994, when RFC was first cloned, tremendous advances in the molecular biology of RFC and biochemical approaches for studying the structure of polytopic membrane proteins have led to an increasingly detailed picture of the molecular structure of the carrier, including its membrane topology, its Nglycosylation, identification of functionally and structurally important domains and amino acids, and helix packing associations. Although no crystal structure for RFC is yet available, biochemical and molecular studies, combined with homology modeling, based on homologous bacterial Major Facilitator Superfamily transporters such as LacY, now permit the development of experimentally testable hypotheses designed to establish RFC structure and mechanism.

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Genetic and nutritional deficiencies in folate metabolism influence tumorigenicity in Apcmin/+ mice

Cited by 18 publications

References 37 publications

Human reduced folate carrier: translation of basic biology to cancer etiology and therapy

Human reduced folate carrier: translation of basic biology to cancer etiology and therapy

The influence of folate and methionine on intestinal tumour development in the ApcMin/+ mouse model

Chapter 5 Structure and Function of the Reduced Folate Carrier

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