| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
J. Biol. Chem., Vol. 276, Issue 43, 39990-40000, October 26, 2001
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
From the Institute of Cancer Biology, Danish Cancer Society,
Strandboulevarden 49, DK-2100 Copenhagen, Denmark
The molecular basis of methotrexate resistance
was studied in human MDA-MB-231 breast cancer cells, which are
inherently defective in methotrexate uptake and lack expression of the
reduced folate carrier (RFC). Transfection of MDA-MB-231 cells with RFC
cDNA restored methotrexate uptake and increased methotrexate
sensitivity by ~50-fold. A CpG island in the promoter region of
RFC was found to be methylated in MDA-MB-231 cells, but was
unmethylated in RFC expressing, methotrexate-sensitive MCF-7 breast
cancer cells. Chromatin immunoprecipitation with antibodies against
acetylated histones H3 and H4 showed that the RFC promoter
was enriched for acetylated histones on expressed, unmethylated alleles
only. Treatment of MDA-MB-231 cells with 5-aza-2'-deoxycytidine
restored RFC expression but also led to increased methotrexate efflux
and did not reverse methotrexate resistance. This suggests that
5-aza-2'-deoxycytidine up-regulates both methotrexate uptake and some
methotrexate-resistance mechanism(s). Reverse transcription-polymerase
chain reaction analysis showed increased expression levels of several
ATP-dependent efflux pumps in response to
5-aza-2'-deoxycytidine treatment, including P-glycoprotein and members
of the multidrug resistance-associated protein family. Up-regulation of
P-glycoprotein in response to 5-aza-2'-deoxycytidine was associated
with demethylation of a CpG island in the MDR1 promoter,
whereas the mechanism(s) for 5-aza-2'-deoxycytidine-induced
up-regulation of multidrug resistance-associated proteins is probably
indirect. Dipyridamole inhibited methotrexate efflux and reversed
methotrexate resistance in 5-aza-2'-deoxycytidine-treated MDA-MB-231 cells.
Methylation-dependent Silencing of the Reduced Folate
Carrier Gene in Inherently Methotrexate-resistant Human Breast Cancer
Cells*
,,, and
*
This work was supported by grants from the Danish Cancer
Society, Danish Medical Research Council, Novo Nordisk Foundation, and
Kaarsen Foundation.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Contributed equally to the results of this work.
§
To whom correspondence and reprint requests should be
addressed: Institute of Cancer Biology, Danish Cancer Society,
Strandboulevarden 49, DK-2100 Copenhagen, Denmark. Tel.: 45-35257500;
Fax: 45-35257721; E-mail: perg@cancer.dk.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  I. Ifergan, G. Jansen, and Y. G. Assaraf The Reduced Folate Carrier (RFC) Is Cytotoxic to Cells under Conditions of Severe Folate Deprivation: RFC AS A DOUBLE EDGED SWORD IN FOLATE HOMEOSTASIS J. Biol. Chem., July 25, 2008; 283(30): 20687 - 20695. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. A. Melnikov, D. M. Scholtens, E. L. Wiley, S. A. Khan, and V. V. Levenson Array-Based Multiplex Analysis of DNA Methylation in Breast Cancer Tissues J. Mol. Diagn., January 1, 2008; 10(1): 93 - 101. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Takeuchi, N. C. Greep, D. S. B. Hoon, A. E. Giuliano, N. M. Hansen, N. Umetani, and F. R. Singer Hypermethylation of Adenosine Triphosphate-Binding Cassette Transporter Genes in Primary Hyperparathyroidism and Its Effect on Sestamibi Imaging J. Clin. Endocrinol. Metab., May 1, 2007; 92(5): 1785 - 1790. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Beckers, S. Organe, L. Timmermans, F. Vanderhoydonc, L. Deboel, R. Derua, E. Waelkens, K. Brusselmans, G. Verhoeven, and J. V. Swinnen Methotrexate enhances the antianabolic and antiproliferative effects of 5-aminoimidazole-4-carboxamide riboside. Mol. Cancer Ther., September 1, 2006; 5(9): 2211 - 2217. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Kaufman, I. Ifergan, L. Rothem, G. Jansen, and Y. G. Assaraf Coexistence of multiple mechanisms of PT523 resistance in human leukemia cells harboring 3 reduced folate carrier alleles: transcriptional silencing, inactivating mutations, and allele loss Blood, April 15, 2006; 107(8): 3288 - 3294. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Liu, Y. Ge, S. G. Payton, A. Aboukameel, S. Buck, R. M. Flatley, C. Haska, R. Mohammad, J. W. Taub, and L. H. Matherly Transcriptional Regulation of the Human Reduced Folate Carrier in Childhood Acute Lymphoblastic Leukemia Cells Clin. Cancer Res., January 15, 2006; 12(2): 608 - 616. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Rothem, B. Berman, M. Stark, G. Jansen, and Y. G. Assaraf The Reduced Folate Carrier Gene Is a Novel Selectable Marker for Recombinant Protein Overexpression Mol. Pharmacol., September 1, 2005; 68(3): 616 - 624. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. A. Melnikov, R. B. Gartenhaus, A. S. Levenson, N. A. Motchoulskaia, and V. V. Levenson (Chernokhvostov) MSRE-PCR for analysis of gene-specific DNA methylation Nucleic Acids Res., June 8, 2005; 33(10): e93 - e93. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Liu, Y. Ge, D. C. Cabelof, A. Aboukameel, A. R. Heydari, R. Mohammad, and L. H. Matherly Structure and Regulation of the Murine Reduced Folate Carrier Gene: IDENTIFICATION OF FOUR NONCODING EXONS AND PROMOTERS AND REGULATION BY DIETARY FOLATES J. Biol. Chem., February 18, 2005; 280(7): 5588 - 5597. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Enokida, H. Shiina, M. Igawa, T. Ogishima, T. Kawakami, W. W. Bassett, J. W. Anast, L.-C. Li, S. Urakami, M. Terashima, et al. CpG Hypermethylation of MDR1 Gene Contributes to the Pathogenesis and Progression of Human Prostate Cancer Cancer Res., September 1, 2004; 64(17): 5956 - 5962. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Huang, P. Anderle, K. J. Bussey, C. Barbacioru, U. Shankavaram, Z. Dai, W. C. Reinhold, A. Papp, J. N. Weinstein, and W. Sadee Membrane Transporters and Channels: Role of the Transportome in Cancer Chemosensitivity and Chemoresistance Cancer Res., June 15, 2004; 64(12): 4294 - 4301. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Zhao, F. Gao, M. Hanscom, and I. D. Goldman A Prominent Low-pH Methotrexate Transport Activity in Human Solid Tumors: Contribution to the Preservation of Methotrexate Pharmacologic Activity in HeLa Cells Lacking the Reduced Folate Carrier Clin. Cancer Res., January 15, 2004; 10(2): 718 - 727. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Misra, S. Ghatak, A. Zoltan-Jones, and B. P. Toole Regulation of Multidrug Resistance in Cancer Cells by Hyaluronan J. Biol. Chem., July 3, 2003; 278(28): 25285 - 25288. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Sowers, J. Toguchida, J. Qin, P. A. Meyers, J. H. Healey, A. Huvos, D. Banerjee, J. R. Bertino, and R. Gorlick mRNA Expression Levels of E2F Transcription Factors Correlate with Dihydrofolate Reductase, Reduced Folate Carrier, and Thymidylate Synthase mRNA Expression in Osteosarcoma Mol. Cancer Ther., June 1, 2003; 2(6): 535 - 541. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Yang, R. Sowers, B. Mazza, J. H. Healey, A. Huvos, H. Grier, M. Bernstein, G. P. Beardsley, M. D. Krailo, M. Devidas, et al. Sequence Alterations in the Reduced Folate Carrier Are Observed in Osteosarcoma Tumor Samples Clin. Cancer Res., February 1, 2003; 9(2): 837 - 844. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |
