title: MytiLec, a Mussel R-Type Lectin, Interacts with Surface Glycan Gb3 on Burkitt's Lymphoma Cells to Trigger Apoptosis through Multiple Pathways.
abstract: 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.
authors.affiliation: Department of Life and Environmental System Science, Graduate School of NanoBio Sciences, Yokohama City University, 22-2 Seto, Kanazawa-ku, Yokohama 236-0027, Japan. hasanimtiaj@yahoo.co.uk.|Department of Biochemistry and Molecular Biology, Faculty of Science, University of Rajshahi, Rajshahi-6205, Bangladesh. hasanimtiaj@yahoo.co.uk.
authors.forename: Imtiaj
authors.initials: I
authors.lastname: Hasan
authors.affiliation: Division of Cell Recognition Study, Institute of Molecular Biomembrane and Glycobiology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. ssuga@tohoku-pharm.ac.jp.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Sugawara
authors.affiliation: Department of Pharmacy, Faculty of Pharmaceutical Science, Nagasaki International University, 2825-7 Huis Ten Bosch, Sasebo, Nagasaki 859-3298, Japan. yfujii@niu.ac.jp.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Fujii
authors.affiliation: Department of Life and Environmental System Science, Graduate School of NanoBio Sciences, Yokohama City University, 22-2 Seto, Kanazawa-ku, Yokohama 236-0027, Japan. yasukoide04@yahoo.co.jp.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Koide
authors.affiliation: Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan. daiki.tera@tsurumi.yokohama-cu.ac.jp.
authors.forename: Daiki
authors.initials: D
authors.lastname: Terada
authors.affiliation: Department of Life and Environmental System Science, Graduate School of NanoBio Sciences, Yokohama City University, 22-2 Seto, Kanazawa-ku, Yokohama 236-0027, Japan. akht.51.314@gmail.com.
authors.forename: Naoya
authors.initials: N
authors.lastname: Iimura
authors.affiliation: Department of Pharmacy, Faculty of Pharmaceutical Science, Nagasaki International University, 2825-7 Huis Ten Bosch, Sasebo, Nagasaki 859-3298, Japan. fujiwara@niu.ac.jp.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Fujiwara
authors.affiliation: Graduate School of Agricultural Science, Tohoku University, 1-1 Amamiya-machi, Tsutsumidori, Aoba-ku, Sendai 230-0045, Japan. keisuke.takahashi.b3@tohoku.ac.jp.
authors.forename: Keisuke G
authors.initials: KG
authors.lastname: Takahashi
authors.affiliation: Department of Life and Environmental System Science, Graduate School of NanoBio Sciences, Yokohama City University, 22-2 Seto, Kanazawa-ku, Yokohama 236-0027, Japan. nobuhiko@yokohama-cu.ac.jp.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Kojima
authors.affiliation: Department of Life and Environmental System Science, Graduate School of NanoBio Sciences, Yokohama City University, 22-2 Seto, Kanazawa-ku, Yokohama 236-0027, Japan. rajia_bio@yahoo.com.|Department of Natural Science, Varendra University, Rajshahi-6204, Bangladesh. rajia_bio@yahoo.com.
authors.forename: Sultana
authors.initials: S
authors.lastname: Rajia
authors.affiliation: Department of Life and Environmental System Science, Graduate School of NanoBio Sciences, Yokohama City University, 22-2 Seto, Kanazawa-ku, Yokohama 236-0027, Japan. akawsarabe@yahoo.com.|Department of Chemistry, Faculty of Sciences, University of Chittagong, Chittagong-4331, Bangladesh. akawsarabe@yahoo.com.
authors.forename: Sarkar M A
authors.initials: SM
authors.lastname: Kawsar
authors.affiliation: Department of Life and Environmental System Science, Graduate School of NanoBio Sciences, Yokohama City University, 22-2 Seto, Kanazawa-ku, Yokohama 236-0027, Japan. kanaly@yokohama-cu.ac.jp.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Kanaly
authors.affiliation: Department of Life and Environmental System Science, Graduate School of NanoBio Sciences, Yokohama City University, 22-2 Seto, Kanazawa-ku, Yokohama 236-0027, Japan. hideho@yokohama-cu.ac.jp.
authors.forename: Hideho
authors.initials: H
authors.lastname: Uchiyama
authors.affiliation: Division of Cell Recognition Study, Institute of Molecular Biomembrane and Glycobiology, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. mhosono@tohoku-pharm.ac.jp.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hosono
authors.affiliation: Department of Pharmacy, Faculty of Pharmaceutical Science, Nagasaki International University, 2825-7 Huis Ten Bosch, Sasebo, Nagasaki 859-3298, Japan. yogawa@niu.ac.jp.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Ogawa
authors.affiliation: Department of Pharmacy, Faculty of Pharmaceutical Science, Nagasaki International University, 2825-7 Huis Ten Bosch, Sasebo, Nagasaki 859-3298, Japan. fujita@niu.ac.jp.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Fujita
authors.affiliation: Department of Biology, School of Health Sciences, Fujita Health University, Toyoake, Aichi 470-1192, Japan. jhamako@fujita-hu.ac.jp.
authors.forename: Jiharu
authors.initials: J
authors.lastname: Hamako
authors.affiliation: Department of Biology, School of Health Sciences, Fujita Health University, Toyoake, Aichi 470-1192, Japan. tmatsui@fujita-hu.ac.jp.
authors.forename: Taei
authors.initials: T
authors.lastname: Matsui
authors.affiliation: Department of Life and Environmental System Science, Graduate School of NanoBio Sciences, Yokohama City University, 22-2 Seto, Kanazawa-ku, Yokohama 236-0027, Japan. ozeki@yokohama-cu.ac.jp.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ozeki
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002051:Burkitt Lymphoma / Q000188:drug therapy* / Q000473:pathology; D002070:Butadienes / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D020014:K562 Cells; D037102:Lectins / Q000302:isolation & purification / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D049878:Mytilus / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D014312:Trisaccharides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D002070:Butadienes; D037102:Lectins; D009570:Nitriles; D014312:Trisaccharides; D014409:Tumor Necrosis Factor-alpha; C113580:U 0126; C113460:globotriose; D020928:Mitogen-Activated Protein Kinases; D053148:Caspase 3; D053453:Caspase 9
keywords: Burkitt’s lymphoma cells; JNK; MEK/ERK; MytiLec; Mytilus galloprovincialis; R-type lectin; TNF-α; caspase-9/3; globotriose (Gb3); p21: p38 kinase; β-trefoil