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Open AccessArticle

MytiLec, a Mussel R-Type Lectin, Interacts with Surface Glycan Gb3 on Burkitt’s Lymphoma Cells to Trigger Apoptosis through Multiple Pathways

1
Department of Life and Environmental System Science, Graduate School of NanoBio Sciences, Yokohama City University, 22-2 Seto, Kanazawa-ku, Yokohama 236-0027, Japan
2
Department of Biochemistry and Molecular Biology, Faculty of Science, University of Rajshahi, Rajshahi-6205, Bangladesh
3
Division of Cell Recognition Study, Institute of Molecular Biomembrane and Glycobiology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan
4
Department of Pharmacy, Faculty of Pharmaceutical Science, Nagasaki International University, 2825-7 Huis Ten Bosch, Sasebo, Nagasaki 859-3298, Japan
5
Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
6
Graduate School of Agricultural Science, Tohoku University, 1-1 Amamiya-machi, Tsutsumidori, Aoba-ku, Sendai 230-0045, Japan
7
Department of Natural Science, Varendra University, Rajshahi-6204, Bangladesh
8
Department of Chemistry, Faculty of Sciences, University of Chittagong, Chittagong-4331, Bangladesh
9
Department of Biology, School of Health Sciences, Fujita Health University, Toyoake, Aichi 470-1192, Japan
*
Author to whom correspondence should be addressed.
These two authors contributed equally to the study and should be considered co-first authors.
Academic Editor: Antonio Trincone
Mar. Drugs 2015, 13(12), 7377-7389; https://doi.org/10.3390/md13127071
Received: 1 October 2015 / Revised: 30 November 2015 / Accepted: 2 December 2015 / Published: 14 December 2015
(This article belongs to the Special Issue Marine Glycoconjugates)
MytiLec; a novel lectin isolated from the Mediterranean mussel (Mytilus galloprovincialis); shows strong binding affinity to globotriose (Gb3: Galα1-4Galβ1-4Glc). MytiLec revealed β-trefoil folding as also found in the ricin B-subunit type (R-type) lectin family, although the amino acid sequences were quite different. Classification of R-type lectin family members therefore needs to be based on conformation as well as on primary structure. MytiLec specifically killed Burkitt's lymphoma Ramos cells, which express Gb3. Fluorescein-labeling assay revealed that MytiLec was incorporated inside the cells. MytiLec treatment of Ramos cells resulted in activation of both classical MAPK/ extracellular signal-regulated kinase and extracellular signal-regulated kinase (MEK-ERK) and stress-activated (p38 kinase and JNK) Mitogen-activated protein kinases (MAPK) pathways. In the cells, MytiLec treatment triggered expression of tumor necrosis factor (TNF)-α (a ligand of death receptor-dependent apoptosis) and activation of mitochondria-controlling caspase-9 (initiator caspase) and caspase-3 (activator caspase). Experiments using the specific MEK inhibitor U0126 showed that MytiLec-induced phosphorylation of the MEK-ERK pathway up-regulated expression of the cyclin-dependent kinase inhibitor p21, leading to cell cycle arrest and TNF-α production. Activation of caspase-3 by MytiLec appeared to be regulated by multiple different pathways. Our findings, taken together, indicate that the novel R-type lectin MytiLec initiates programmed cell death of Burkitt’s lymphoma cells through multiple pathways (MAPK cascade, death receptor signaling; caspase activation) based on interaction of the lectin with Gb3-containing glycosphingolipid-enriched microdomains on the cell surface. View Full-Text
Keywords: Burkitt’s lymphoma cells; caspase-9/3; globotriose (Gb3); JNK; Mytilus galloprovincialis; MEK/ERK; MytiLec; p21: p38 kinase; R-type lectin; TNF-α; β-trefoil Burkitt’s lymphoma cells; caspase-9/3; globotriose (Gb3); JNK; Mytilus galloprovincialis; MEK/ERK; MytiLec; p21: p38 kinase; R-type lectin; TNF-α; β-trefoil
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Hasan, I.; Sugawara, S.; Fujii, Y.; Koide, Y.; Terada, D.; Iimura, N.; Fujiwara, T.; Takahashi, K.G.; Kojima, N.; Rajia, S.; Kawsar, S.M.A.; Kanaly, R.A.; Uchiyama, H.; Hosono, M.; Ogawa, Y.; Fujita, H.; Hamako, J.; Matsui, T.; Ozeki, Y. MytiLec, a Mussel R-Type Lectin, Interacts with Surface Glycan Gb3 on Burkitt’s Lymphoma Cells to Trigger Apoptosis through Multiple Pathways. Mar. Drugs 2015, 13, 7377-7389.

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