Skip to main content
SpringerLink
Log in

Hormonal Control of Folate Receptor Genes

  • Chapter
  • First Online:
Targeted Drug Strategies for Cancer and Inflammation

  • 877 Accesses

Abstract

The two major human folate receptor (FR) isoforms, α and β, are glycosyl phosphatidylinositol-anchored glycoproteins with limited expression in normal tissues including epithelial cells (FRα) and hematopoietic cells (FRβ). FRα plays a critical role during pregnancy in ensuring an adequate supply of folate to the fetus. FRs are a potential means of delivering a range of therapeutics in cancer and inflammatory diseases in a tissue-targeted manner. The FRα gene is under the exquisite control of steroid hormones which regulate the protein expression by diverse and nonclassical molecular mechanisms. The FRβ gene on the other hand is regulated by retinoid compounds through a nonclassical mechanism. The physiological mechanisms of FR gene regulation could be utilized to selectively enhance the receptor expression and consequently drug delivery to the target tissues. The soluble form of FRα may also be effectively utilized in this manner as a serum marker in the early detection of certain cancers. The in vitro and animal model studies in this field have advanced to a stage that warrants direct clinical trials to validate the proposed treatment modalities.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • An J, Ribeiro RC, Webb P, Gustafsson JA, Kushner PJ, Baxter JD et al (1999) Estradiol repression of tumor necrosis factor-alpha transcription requires estrogen receptor activation function-2 and is enhanced by coactivators. Proc Natl Acad Sci USA 96(26):15161–15166

    Article  PubMed  CAS  Google Scholar 

  • Antony AC (1992) The biological chemistry of folate receptors. Blood 79(11):2807–2820

    PubMed  CAS  Google Scholar 

  • Barber RC, Bennett GD, Greer KA, Finnell RH (1999) Expression patterns of folate binding proteins one and two in the developing mouse embryo. Mol Genet Metab 66(1):31–39

    Article  PubMed  CAS  Google Scholar 

  • Blaser BW, Gonit M, Qi H, Shatnawi A, Guimond M, Lee RJ et al (2007) Induction of folate receptor type beta in a bone marrow engraftment model of acute myelogenous leukemia. Leukemia 21(10):2233–2235

    Article  PubMed  CAS  Google Scholar 

  • Bueno R, Appasani K, Mercer H, Lester S, Sugarbaker D (2001) The alpha folate receptor is highly activated in malignant pleural mesothelioma. J Thorac Cardiovasc Surg 121(2):225–233

    Article  PubMed  CAS  Google Scholar 

  • Cerillo G, Rees A, Manchanda N, Reilly C, Brogan I, White A et al (1998) The oestrogen receptor regulates NFkappaB and AP-1 activity in a cell-specific manner. J Steroid Biochem Mol Biol 67(2):79–88

    Article  PubMed  CAS  Google Scholar 

  • Chancy CD, Kekuda R, Huang W, Prasad PD, Kuhnel JM, Sirotnak FM et al (2000) Expression and differential polarization of the reduced-folate transporter-1 and the folate receptor alpha in mammalian retinal pigment epithelium. J Biol Chem 275(27):20676–20684

    Article  PubMed  CAS  Google Scholar 

  • Chen JD, Evans RM (1995) A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature 377(6548):454–457

    Article  PubMed  CAS  Google Scholar 

  • Chen H, Lin RJ, Schiltz RL, Chakravarti D, Nash A, Nagy L et al (1997) Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Cell 90(3):569–580

    Article  PubMed  CAS  Google Scholar 

  • Cloke B, Huhtinen K, Fusi L, Kajihara T, Yliheikkila M, Ho KK et al (2008) The androgen and progesterone receptors regulate distinct gene networks and cellular functions in decidualizing endometrium. Endocrinology 149(9):4462–4474

    Article  PubMed  CAS  Google Scholar 

  • Critchley HO, Saunders PT (2009) Hormone receptor dynamics in a receptive human ­endometrium. Reprod Sci 16(2):191–199

    Article  PubMed  CAS  Google Scholar 

  • Elgort MG, Zou A, Marschke KB, Allegretto EA (1996) Estrogen and estrogen receptor antagonists stimulate transcription from the human retinoic acid receptor-alpha 1 promoter via a novel sequence. Mol Endocrinol 10(5):477–487

    Article  PubMed  CAS  Google Scholar 

  • Elnakat H, Ratnam M (2004) Distribution, functionality and gene regulation of folate receptor isoforms: implications in targeted therapy. Adv Drug Deliv Rev 56(8):1067–1084

    Article  PubMed  CAS  Google Scholar 

  • Elnakat H, Gonit M, Salazar MD, Zhang J, Basrur V, Gunning W et al (2009) Regulation of folate receptor internalization by protein kinase C alpha. Biochemistry 48(34):8249–8260

    Article  PubMed  CAS  Google Scholar 

  • Elwood PC (1989) Molecular cloning and characterization of the human folate-binding protein cDNA from placenta and malignant tissue culture (KB) cells. J Biol Chem 264(25):14893–14901

    PubMed  CAS  Google Scholar 

  • Elwood PC, Nachmanoff K, Saikawa Y, Page ST, Pacheco P, Roberts S et al (1997) The divergent 5′ termini of the alpha human folate receptor (hFR) mRNAs originate from two tissue-specific promoters and alternative splicing: characterization of the alpha hFR gene structure. Biochemistry 36(6):1467–1478

    Article  PubMed  CAS  Google Scholar 

  • Evans CO, Young AN, Brown MR, Brat DJ, Parks JS, Neish AS et al (2001) Novel patterns of gene expression in pituitary adenomas identified by complementary deoxyribonucleic acid microarrays and quantitative reverse transcription-polymerase chain reaction. J Clin Endocrinol Metab 86(7):3097–3107

    Article  PubMed  CAS  Google Scholar 

  • Figini M, Ferri R, Mezzanzanica D, Bagnoli M, Luison E, Miotti S et al (2003) Reversion of transformed phenotype in ovarian cancer cells by intracellular expression of anti folate receptor antibodies. Gene Ther 10(12):1018–1025

    Article  PubMed  CAS  Google Scholar 

  • Finnell RH, Wlodarczyk B, Spiegelstein O, Triplett A, GelineauvanWaes J (2001) Folate transport abnormalities and congenital defects. Kluwer Academic publishers, Norwich

    Google Scholar 

  • Hao H, Qi H, Ratnam M (2003) Modulation of the folate receptor type beta gene by coordinate actions of retinoic acid receptors at activator Sp1/ets and repressor AP-1 sites. Blood 101(11):4551–4560

    Article  PubMed  CAS  Google Scholar 

  • Hao H, d’Alincourt-Salazar M, Kelley KM, Shatnawi A, Mukherjee S, Shah YM et al (2007) Estrogen-induced and TAFII30-mediated gene repression by direct recruitment of the estrogen receptor and co-repressors to the core promoter and its reversal by tamoxifen. Oncogene 26(57):7872–7884

    Article  PubMed  CAS  Google Scholar 

  • Harnish DC, Scicchitano MS, Adelman SJ, Lyttle CR, Karathanasis SK (2000) The role of CBP in estrogen receptor cross-talk with nuclear factor-kappaB in HepG2 cells. Endocrinology 141(9):3403–3411

    Article  PubMed  CAS  Google Scholar 

  • Horlein AJ, Naar AM, Heinzel T, Torchia J, Gloss B, Kurokawa R et al (1995) Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor. Nature 377(6548):397–404

    Article  PubMed  CAS  Google Scholar 

  • Hu X, Lazar MA (1999) The CoRNR motif controls the recruitment of corepressors by nuclear hormone receptors. Nature 402(6757):93–96

    Article  PubMed  CAS  Google Scholar 

  • Jakacka M, Ito M, Weiss J, Chien PY, Gehm BD, Jameson JL (2001) Estrogen receptor binding to DNA is not required for its activity through the nonclassical AP1 pathway. J Biol Chem 276(17):13615–13621

    PubMed  CAS  Google Scholar 

  • Kamen BA, Smith AK (2004) A review of folate receptor alpha cycling and 5-methyltetrahydrofolate accumulation with an emphasis on cell models in vitro. Adv Drug Deliv Rev 56(8):1085–1097

    Article  PubMed  CAS  Google Scholar 

  • Kelley KM, Rowan BG, Ratnam M (2003) Modulation of the folate receptor alpha gene by the estrogen receptor: mechanism and implications in tumor targeting. Cancer Res 63(11):2820–2828

    PubMed  CAS  Google Scholar 

  • Lacey SW, Sanders JM, Rothberg KG, Anderson RG, Kamen BA (1989) Complementary DNA for the folate binding protein correctly predicts anchoring to the membrane by glycosyl-phosphatidylinositol. J Clin Invest 84(2):715–720

    Article  PubMed  CAS  Google Scholar 

  • Low PS, Henne WA, Doorneweerd DD (2008) Discovery and development of folic-acid-based receptor targeting for imaging and therapy of cancer and inflammatory diseases. Acc Chem Res 41(1):120–129

    Article  PubMed  CAS  Google Scholar 

  • Mantovani LT, Miotti S, Menard S, Canevari S, Raspagliesi F, Bottini C et al (1994) Folate binding protein distribution in normal tissues and biological fluids from ovarian carcinoma patients as detected by the monoclonal antibodies MOv18 and MOv19. Eur J Cancer 30A(3):363–369

    Article  PubMed  CAS  Google Scholar 

  • McKenna NJ, Lanz RB, O’Malley BW (1999) Nuclear receptor coregulators: cellular and molecular biology. Endocr Rev 20(3):321–344

    Article  PubMed  CAS  Google Scholar 

  • Milne SA, Henderson TA, Kelly RW, Saunders PT, Baird DT, Critchley HO (2005) Leukocyte populations and steroid receptor expression in human first-trimester decidua; regulation by antiprogestin and prostaglandin E analog. J Clin Endocrinol Metab 90(7):4315–4321

    Article  PubMed  CAS  Google Scholar 

  • Moggs JG, Orphanides G (2001) Estrogen receptors: orchestrators of pleiotropic cellular responses. EMBO Rep 2(9):775–781

    Article  PubMed  CAS  Google Scholar 

  • Molloy AM, Scott JM (2001) Folates and prevention of disease. Public Health Nutr 4(2B):601–609

    Article  PubMed  CAS  Google Scholar 

  • Nakashima-Matsushita N, Homma T, Yu S, Matsuda T, Sunahara N, Nakamura T et al (1999) Selective expression of folate receptor beta and its possible role in methotrexate transport in synovial macrophages from patients with rheumatoid arthritis. Arthritis Rheum 42(8):1609–1616

    Article  PubMed  CAS  Google Scholar 

  • Paech K, Webb P, Kuiper GG, Nilsson S, Gustafsson J, Kushner PJ et al (1997) Differential ligand activation of estrogen receptors ERalpha and ERbeta at AP1 sites. Science 277(5331):1508–1510

    Article  PubMed  CAS  Google Scholar 

  • Pan XQ, Zheng X, Shi G, Wang H, Ratnam M, Lee RJ (2002) Strategy for the treatment of acute myelogenous leukemia based on folate receptor beta-targeted liposomal doxorubicin combined with receptor induction using all-trans retinoic acid. Blood 100(2):594–602

    Article  PubMed  CAS  Google Scholar 

  • Piedrahita JA, Oetama B, Bennett GD, van Waes J, Kamen BA, Richardson J et al (1999) Mice lacking the folic acid-binding protein Folbp1 are defective in early embryonic development. Nat Genet 23(2):228–232

    Article  PubMed  CAS  Google Scholar 

  • Qi H, Ratnam M (2006) Synergistic induction of folate receptor beta by all-trans retinoic acid and histone deacetylase inhibitors in acute myelogenous leukemia cells: mechanism and utility in enhancing selective growth inhibition by antifolates. Cancer Res 66(11):5875–5882

    Article  PubMed  CAS  Google Scholar 

  • Ragoussis J, Senger G, Trowsdale J, Campbell IG (1992) Genomic organization of the human folate receptor genes on chromosome 11q13. Genomics 14(2):423–430

    Article  PubMed  CAS  Google Scholar 

  • Ramji DP, Foka P (2002) CCAAT/enhancer-binding proteins: structure, function and regulation. Biochem J 365(Pt 3):561–575

    PubMed  CAS  Google Scholar 

  • Ratnam M, Marquardt H, Duhring JL, Freisheim JH (1989) Homologous membrane folate binding proteins in human placenta: cloning and sequence of a cDNA. Biochemistry 28(20):8249–8254

    Article  PubMed  CAS  Google Scholar 

  • Ratnam M, Hao H, Zheng X, Wang H, Qi H, Lee R et al (2003) Receptor induction and targeted drug delivery: a new antileukaemia strategy. Expert Opin Biol Ther 3(4):563–574

    Article  PubMed  CAS  Google Scholar 

  • Reddy JA, Haneline LS, Srour EF, Antony AC, Clapp DW, Low PS (1999) Expression and functional characterization of the beta-isoform of the folate receptor on CD34(+) cells. Blood 93(11):3940–3948

    PubMed  CAS  Google Scholar 

  • Roberts SJ, Chung KN, Nachmanoff K, Elwood PC (1997) Tissue-specific promoters of the alpha human folate receptor gene yield transcripts with divergent 5′ leader sequences and different translational efficiencies. Biochem J 326(Pt 2):439–447

    PubMed  CAS  Google Scholar 

  • Rochman H, Selhub J, Karrison T (1985) Folate binding protein and the estrogen receptor in breast cancer. Cancer Detect Prev 8(1–2):71–75

    PubMed  CAS  Google Scholar 

  • Ross JF, Chaudhuri PK, Ratnam M (1994) Differential regulation of folate receptor isoforms in normal and malignant tissues in vivo and in established cell lines. Physiologic and clinical implications. Cancer 73(9):2432–2443

    Article  PubMed  CAS  Google Scholar 

  • Ross JF, Wang H, Behm FG, Mathew P, Wu M, Booth R et al (1999) Folate receptor type beta is a neutrophilic lineage marker and is differentially expressed in myeloid leukemia. Cancer 85(2):348–357

    Article  PubMed  CAS  Google Scholar 

  • Sabharanjak S, Sharma P, Parton RG, Mayor S (2002) GPI-anchored proteins are delivered to recycling endosomes via a distinct cdc42-regulated, clathrin-independent pinocytic pathway. Dev Cell 2(4):411–423

    Article  PubMed  CAS  Google Scholar 

  • Sadasivan E, Cedeno MM, Rothenberg SP (1994) Characterization of the gene encoding a folate-binding protein expressed in human placenta. Identification of promoter activity in a G-rich SP1 site linked with the tandemly repeated GGAAG motif for the ets encoded GA-binding protein. J Biol Chem 269(7):4725–4735

    PubMed  CAS  Google Scholar 

  • Safe S (2001) Transcriptional activation of genes by 17 beta-estradiol through estrogen receptor-Sp1 interactions. Vitam Horm 62:231–252

    Article  PubMed  CAS  Google Scholar 

  • Saikawa Y, Price K, Hance KW, Chen TY, Elwood PC (1995) Structural and functional analysis of the human KB cell folate receptor gene P4 promoter: cooperation of three clustered Sp1-binding sites with initiator region for basal promoter activity. Biochemistry 34(31):9951–9961

    Article  PubMed  CAS  Google Scholar 

  • Salazar MD, Ratnam M (2007) The folate receptor: what does it promise in tissue-targeted therapeutics? Cancer Metastasis Rev 26(1):141–152

    Article  PubMed  CAS  Google Scholar 

  • Salbaum JM, Finnell RH, Kappen C (2009) Regulation of folate receptor 1 gene expression in the visceral endoderm. Birth Defects Res A Clin Mol Teratol 85(4):303–313

    Article  PubMed  CAS  Google Scholar 

  • Schule R, Umesono K, Mangelsdorf DJ, Bolado J, Pike JW, Evans RM (1990) Jun-Fos and receptors for vitamins A and D recognize a common response element in the human osteocalcin gene. Cell 61(3):497–504

    Article  PubMed  CAS  Google Scholar 

  • Shatnawi A, Tran T, Ratnam M (2007) R5020 and RU486 act as progesterone receptor agonists to enhance Sp1/Sp4-dependent gene transcription by an indirect mechanism. Mol Endocrinol 21(3):635–650

    Article  PubMed  CAS  Google Scholar 

  • Steinfeld R, Grapp M, Kraetzner R, Dreha-Kulaczewski S, Helms G, Dechent P et al (2009) Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism. Am J Hum Genet 85(3):354–363

    Article  PubMed  CAS  Google Scholar 

  • Stoner M, Wang F, Wormke M, Nguyen T, Samudio I, Vyhlidal C et al (2000) Inhibition of vascular endothelial growth factor expression in HEC1A endometrial cancer cells through interactions of estrogen receptor alpha and Sp3 proteins. J Biol Chem 275(30):22769–22779

    Article  PubMed  CAS  Google Scholar 

  • Toffoli G, Cernigoi C, Russo A, Gallo A, Bagnoli M, Boiocchi M (1997) Overexpression of folate binding protein in ovarian cancers. Int J Cancer 74(2):193–198

    Article  PubMed  CAS  Google Scholar 

  • Tran T, Shatnawi A, Zheng X, Kelley KM, Ratnam M (2005) Enhancement of folate receptor alpha expression in tumor cells through the glucocorticoid receptor: a promising means to improved tumor detection and targeting. Cancer Res 65(10):4431–4441

    Article  PubMed  CAS  Google Scholar 

  • Umesono K, Giguere V, Glass CK, Rosenfeld MG, Evans RM (1988) Retinoic acid and thyroid hormone induce gene expression through a common responsive element. Nature 336(6196):262–265

    Article  PubMed  CAS  Google Scholar 

  • Wang X, Shen F, Freisheim JH, Gentry LE, Ratnam M (1992) Differential stereospecificities and affinities of folate receptor isoforms for folate compounds and antifolates. Biochem Pharmacol 44(9):1898–1901

    Article  PubMed  CAS  Google Scholar 

  • Wang H, Zheng X, Behm FG, Ratnam M (2000) Differentiation-independent retinoid induction of folate receptor type beta, a potential tumor target in myeloid leukemia. Blood 96(10):3529–3536

    PubMed  CAS  Google Scholar 

  • Wang J, Gunning W, Kelley KM, Ratnam M (2002) Evidence for segregation of heterologous GPI-anchored proteins into separate lipid rafts within the plasma membrane. J Membr Biol 189(1):35–43

    Article  PubMed  CAS  Google Scholar 

  • Webb P, Nguyen P, Valentine C, Lopez GN, Kwok GR, McInerney E et al (1999) The estrogen receptor enhances AP-1 activity by two distinct mechanisms with different requirements for receptor transactivation functions. Mol Endocrinol 13(10):1672–1685

    Article  PubMed  CAS  Google Scholar 

  • Weitman SD, Weinberg AG, Coney LR, Zurawski VR, Jennings DS, Kamen BA (1992) Cellular localization of the folate receptor: potential role in drug toxicity and folate homeostasis. Cancer Res 52(23):6708–6711

    PubMed  CAS  Google Scholar 

  • Wu M, Gunning W, Ratnam M (1999) Expression of folate receptor type alpha in relation to cell type, malignancy, and differentiation in ovary, uterus, and cervix. Cancer Epidemiol Biomarkers Prev 8(9):775–782

    PubMed  CAS  Google Scholar 

  • Xu L, Glass CK, Rosenfeld MG (1999) Coactivator and corepressor complexes in nuclear receptor function. Curr Opin Genet Dev 9(2):140–147

    Article  PubMed  CAS  Google Scholar 

  • Yan W, Ratnam M (1995) Preferred sites of glycosylphosphatidylinositol modification in folate receptors and constraints in the primary structure of the hydrophobic portion of the signal. Biochemistry 34(44):14594–14600

    Article  PubMed  CAS  Google Scholar 

  • Yang NN, Venugopalan M, Hardikar S, Glasebrook A (1997) Correction: raloxifene response needs more than an element. Science 275(5304):1249

    Article  PubMed  CAS  Google Scholar 

  • Zhao R, Min SH, Wang Y, Campanella E, Low PS, Goldman ID (2009) A role for the proton-coupled folate transporter (PCFT-SLC46A1) in folate receptor-mediated endocytosis. J Biol Chem 284(7):4267–4274

    Article  PubMed  CAS  Google Scholar 

  • Zou A, Marschke KB, Arnold KE, Berger EM, Fitzgerald P, Mais DE et al (1999) Estrogen receptor beta activates the human retinoic acid receptor alpha-1 promoter in response to tamoxifen and other estrogen receptor antagonists, but not in response to estrogen. Mol Endocrinol 13(3):418–430

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This work was supported by NIH R01 grants CA 103964 and CA 80183 and by the Harold and Helen McMaster endowment to M.R.

Author information

Authors and Affiliations

  1. Department of Biochemistry and Cancer Biology, University of Toledo College of Medicine, 3000 Arlington Avenue, Toledo, OH, 43614, USA

    Manohar Ratnam

Authors
  1. Mesfin Gonit
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marcela D’Alincourt Salazar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Juan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hala Elnakat
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Suneethi Sivakumaran
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Manohar Ratnam
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Manohar Ratnam .

Editor information

Editors and Affiliations

  1. Section of Medicine, Institute of Cancer Research, Cotswold Road 15, Sutton, SM2 5NG, United Kingdom

    Ann L. Jackman

  2. Endocyte Inc., Kent Avenue 3000, West Lafayette, 47906, Indiana, USA

    Christopher P. Leamon

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Gonit, M., Salazar, M.D., Zhang, J., Elnakat, H., Sivakumaran, S., Ratnam, M. (2011). Hormonal Control of Folate Receptor Genes. 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_3

Download citation

Publish with us

Policies and ethics

Search

Navigation