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

• Published in: Marine drugs 2015-12, Vol.13 (12), p.7377-7389
• Main Authors: Hasan, Imtiaj, Sugawara, Shigeki, Fujii, Yuki, Koide, Yasuhiro, Terada, Daiki, Iimura, Naoya, Fujiwara, Toshiyuki, Takahashi, Keisuke G, Kojima, Nobuhiko, Rajia, Sultana, Kawsar, Sarkar M A, Kanaly, Robert A, Uchiyama, Hideho, Hosono, Masahiro, Ogawa, Yukiko, Fujita, Hideaki, Hamako, Jiharu, Matsui, Taei, Ozeki, Yasuhiro
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Burkitt Lymphoma - drug therapy; Burkitt Lymphoma - pathology; Burkitt’s lymphoma cells; Butadienes - pharmacology; Caspase 3 - metabolism; Caspase 9 - metabolism; caspase-9/3; Cell Line, Tumor; globotriose (Gb3); Humans; JNK; K562 Cells; Lectins - isolation & purification; Lectins - pharmacology; MEK/ERK; Mitogen-Activated Protein Kinases - metabolism; MytiLec; Mytilus - metabolism; Mytilus galloprovincialis; Nitriles - pharmacology; p21: p38 kinase; R-type lectin; TNF-α; Trisaccharides - metabolism; Tumor Necrosis Factor-alpha - metabolism; β-trefoil
• ISSN: 1660-3397; 1660-3397
• DOI: 10.3390/md13127071

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.