A synthetic glycosphingolipid-induced antiproliferative effect in melanoma cells is associated with suppression of FAK, Akt, and Erk activation.
Numerous studies have demonstrated the participation of glicolipids in signal transduction and the regulation of melanoma cell growth and apoptosis. Hoping to discover new anticancer drugs, we have synthesized ten glycolipids found in various invertebrates that do not have sialic acids. These compounds were tested for antiproliferative effects on a melanoma cell line, B16F10. A synthetic compound, Manbeta(1-4)[Fucalpha(1-3)]Glcbeta1-Cer, (glycosphingolipid 7), which was identified in the millipede Parafontaria laminata armigera, had an antiproliferative effect on the melanoma cells. This compound suppressed the activation of the focal adhesion kinase (FAK)-Akt pathway as well as the activation of extracellular signal-regulated kinase (Erk)1/2 pathway involved in cell proliferation. Expression of the cell cycle proteins, cyclin D1 and CDK4, was suppressed by glycosphingolipid 7. From these results, glycosphingolipid 7 suppressed the activation of the FAK-Akt pathway and of Erk1/2, which resulted in a decrease in the expression of cyclin D1 and CDK4. Glycosphingolipid 7 might be a candidate for an inhibitor of cell proliferation in melanomas.
Department of Biochemistry and Pharmacognosy, Kyoritsu University of Pharmacy, Tokyo, Japan. sonoda-ys@pha.keio.ac.jp
Yoshiko
Y
Sonoda
Noriyasu
N
Hada
Tomonori
T
Kaneda
Takaharu
T
Suzuki
Tomoyuki
T
Ohshio
Tadahiro
T
Takeda
Tadashi
T
Kasahara
D000818:Animals; D000970:Antineoplastic Agents; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics; D003627:Data Interpretation, Statistical; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000502:physiology; D006028:Glycosphingolipids / Q000494:pharmacology*; D047468:Immunoprecipitation; D007202:Indicators and Reagents; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D051058:Oncogene Protein v-akt / Q000502:physiology; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism
D000970:Antineoplastic Agents; D006028:Glycosphingolipids; D007202:Indicators and Reagents; D016160:Retinoblastoma Protein; D019938:Cyclin D1; D007770:L-Lactate Dehydrogenase; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051058:Oncogene Protein v-akt; D048049:Extracellular Signal-Regulated MAP Kinases