期刊
MARINE DRUGS
卷 13, 期 12, 页码 7377-7389出版社
MDPI
DOI: 10.3390/md13127071
关键词
Burkitt's lymphoma cells; caspase-9/3; globotriose (Gb3); JNK; Mytilus galloprovincialis; MEK/ERK; MytiLec; p21: p38 kinase; R-type lectin; TNF-alpha; beta-trefoil
资金
- Japan Society for the Promotion of Science (JSPS)
- Academic Frontier Project for Private Universities
- Strategic Project to Support the Formation of Research Bases at Private Universities from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT)
- Science Research Promotion Fund from The Promotion and Mutual Aid Corporation for Private Schools
- Yokohama City University, Japan
- Grants-in-Aid for Scientific Research [25450306, 25840119, 26505010, 25461463] Funding Source: KAKEN
MytiLec; a novel lectin isolated from the Mediterranean mussel (Mytilus galloprovincialis); shows strong binding affinity to globotriose (Gb3: Gal1-4Gal1-4Glc). MytiLec revealed -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)- (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- 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.
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