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MRP1 Expressed on Burkitt’s Lymphoma Cells was Depleted by Catfish Egg Lectin Through Gb3-Glycosphingolipid and Enhanced Cytotoxic Effect of Drugs

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Abstract

A novel anticancer mechanism of catfish (Silurus asotus) egg lectin (SAL) was found to occur via the down-regulation of the membrane transopter protein, MRP1 (multidrug resistance associate protein-1) on Burkitt’s lymphoma cells through Gb3(Galα1-4Galβ1-4Glc)-glycosphingolipid. Although SAL did not influence the viability of the cells directly, only 10 and 100 ng/mL of vincristine and etoposide, respectively induced anticancer effects when the lectin was applied in conjunction with these drugs. These phenomena were specifically inhibited by the co-presence of the α-galactoside, melibiose, which is a strong haptenic sugar of SAL that mimicks Gb3. The degree of expression regulation of the transporter proteins on the cells surface was investigated through the examination of the binding between SAL and Gb3-glycosphingolipid by immunological and molecular biological procedures. PCR data showed that MRP1 was more highly expressed when compared to another ATP-binding cassette family, multi-drug resistant protein and the expression levels of MRP1 on the cells were specifically dose- and time-dependently depleted by the addition of SAL. These results were also evaluated by immunological procedures using FACS and western-blotting. Small interfering RNA coding a part of MRP1 was transfected to Raji cells to knock down the protein, and cell death was increased by 10% when vincristine was administered at a concentration as low as 10 ng/mL compared to non-transfected cells. These results indicated that SAL possesses the potential to enhance the anticancer activites of low-concentrations of vincristine by the down-regulating the MRP1 gene expression to inhibit the multidrug resistance by binding to the target ligand Gb3-glycosphingolipid on Burkitt’s lymphoma cells.

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Abbreviations

ABC transporter:

ATP-binding cassette transporter

GAPDH:

Glycelardehyde-3-phosphate dehydrogenase

Gb3:

Globotriose (Galα1-4Galβ1-4Glc)

GEM:

Glycosphingolipid enriched microdomain

CRD:

Carbohydrate recognition domain

GSL:

Glycosphingolipid

FACS:

Fluorescence activated cell sorter

MDR1:

Multidrug resistance protein 1

MRP1:

Multidrug resistance associate protein 1

RIPA:

Radio-immuno-precipitation assay

RT-PCR:

Reverse transcription polymerase chain reaction

SAL:

Silurus asotus lectin

SBL:

Sialic acid binding lectin

siRNA:

Small interfering RNA

SUEL:

Sea urchin unfertilized eggs lectin

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Acknowledgments

This work was supported by the Grants-in-Aid for Frontier Research Program from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) Japan; Grants-in-Aid for Japan Society for the Promotion of Science (JSPS) Fellows, and Scientific Research.

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Author notes

  1. Yuki Fujii

    Present address: Department of Genetics, Cell Biology and Development, University of Minnesota, 321 Church St. SE, Minneapolis, MN, 55455, USA

Authors and Affiliations

  1. Division of Cell Recognition Study, Institute of Molecular Biomembrane and Glycobiology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-Ku, Sendai, 981-8558, Japan

    Yuki Fujii, Shigeki Sugawara, Daisuke Araki, Tasuku Kawano, Takeo Tatsuta, Masahiro Hosono, Motoaki Takayanagi & Kazuo Nitta

  2. Division of Cancer Glycosylation Research, Institute of Molecular Biomembrane and Glycobiology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-Ku, Sendai, 981-8558, Japan

    Kohta Takahashi, Taeko Miyagi & Motoaki Takayanagi

  3. Laboratory of Glycobiology and Marine Biochemistry, Department of Genome System Sciences, Graduate School of NanoBiosciences, Yokohama City University, Yokohama, 236-0027, Japan

    Yuki Fujii, Sarkar M. A. Kawsar, Ryo Matsumoto, Hidetaro Yasumitsu & Yasuhiro Ozeki

  4. Department of Chemistry, Graduate School of Sciences, The University of Chittagong, Chittagong, 4331, Bangladesh

    Sarkar M. A. Kawsar

  5. Laboratory of Environmental Microbiology and Molecular Toxicology, Department of Genome System Sciences, Graduate School of NanoBiosciences, Yokohama City University, 22-2 Seto, Kanazawa-ku, Yokohama, 236-0027, Japan

    Robert A. Kanaly

  6. Division of Biomembrane Research, Pacific Northwest Research Institute, 720 Broadway, Seattle, WA, 98122, USA

    Sen-itiroh Hakomori

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  1. Yuki Fujii
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  2. Shigeki Sugawara
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  7. Sarkar M. A. Kawsar
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Corresponding author

Correspondence to Yuki Fujii.

Additional information

Yuki Fujii and Shigeki Sugawara have equally contributed as the first author.

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Fujii, Y., Sugawara, S., Araki, D. et al. MRP1 Expressed on Burkitt’s Lymphoma Cells was Depleted by Catfish Egg Lectin Through Gb3-Glycosphingolipid and Enhanced Cytotoxic Effect of Drugs. Protein J 31, 15–26 (2012). https://doi.org/10.1007/s10930-011-9369-2

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