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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.

Vibrio vulnificus cytolysin (VVC) has a very strong cytotoxic effect on various types of mammalian cells. However, the inhibitory effect of VVC on the proliferation of human lung cancer cells has scarcely been reported. This study aimed to analyze the effects of recombinant VVC (rVVC) on the A549 human lung adenocarcinoma cell line and to investigate the underlying molecular mechanisms governing these effects. This study showed that rVVC inhibited the proliferation of A549 cells in a concentration- and time-dependent manner (as measured by the MTT assay). rVVC failed to induce the release of intracellular lactate dehydrogenase (LDH) from the target cells suggesting that osmotic lysis may not contribute to its cytolysin-induced cytotoxicity. Treatment of A549 cells with an IC50 (concentration of drug that inhibits cell growth by 50%) of rVVC resulted in morphological changes and blebbing typical of apoptosis. Annexin-V FITC analysis by FCM indicated that rVVC-induced apoptosis in A549 cells occurs in a dose-dependent manner. A DNA fragmentation assay was utilized to investigate the apoptosis induced by rVVC. The pro-apoptotic activity of rVVC was attributed to its ability to modulate, in a concerted manner, the expression of Bcl-2 and Bax proteins, which were down- and up-regulated, respectively. Caspase-9 and -3 were subsequently activated, however caspase-8 was not. These results prove that rVVC effectively induces programmed cell death and suggests that rVVC-induced apoptosis in the A549 cell line is mediated by the regulation of Bcl-2 protein expression and the activation of caspase-9 and -3.