title: Ganglioside GM2 mediates migration of tumor cells by interacting with integrin and modulating the downstream signaling pathway.
abstract: The definitive role of ganglioside GM2 in mediating tumor-induced growth and progression is still unknown. Here we report a novel role of ganglioside GM2 in mediating tumor cell migration and uncovered its mechanism. Data shows differential expression levels of GM2-synthase as well as GM2 in different human cancer cells. siRNA mediated knockdown of GM2-synthase in CCF52, A549 and SK-RC-26B cells resulted in significant inhibition of tumor cell migration as well as invasion in vitro without affecting cellular proliferation. Over-expression of GM2-synthase in low-GM2 expressing SK-RC-45 cells resulted in a consequent increase in migration thus confirming the potential role GM2 and its downstream partners play in tumor cell migration and motility. Further, treatment of SK-RC-45 cells with exogenous GM2 resulted in a dramatic increase in migratory and invasive capacity with no change in proliferative capacity, thereby confirming the role of GM2 in tumorigenesis specifically by mediating tumor migration and invasion. Gene expression profiling of GM2-synthase silenced cells revealed altered expression of several genes involved in cell migration primarily those controlling the integrin mediated signaling. GM2-synthase knockdown resulted in decreased phosphorylation of FAK, Src as well as Erk, while over-expression and/or exogenous GM2 treatment caused increased FAK and Erk phosphorylation respectively. Again, GM2 mediated invasion and Erk phosphorylation is blocked in integrin knockdown SK-RC-45 cells, thus confirming that GM2 mediated migration and phosphorylation of Erk is integrin dependent. Finally, confocal microscopy suggested co-localization while co-immunoprecipitation and surface plasmon resonance (SPR) confirmed direct interaction of membrane bound ganglioside, GM2 with the integrin receptor.
authors.affiliation: Division of Molecular Medicine, Bose Institute, Kolkata, West Bengal 700054, India.
authors.forename: Manjari
authors.initials: M
authors.lastname: Kundu
authors.affiliation: Division of Molecular Medicine, Bose Institute, Kolkata, West Bengal 700054, India.
authors.forename: Barun
authors.initials: B
authors.lastname: Mahata
authors.affiliation: Division of Molecular Medicine, Bose Institute, Kolkata, West Bengal 700054, India.
authors.forename: Avisek
authors.initials: A
authors.lastname: Banerjee
authors.affiliation: The Bioinformatics Center, Bose Institute, Kolkata, West Bengal 700054, India.
authors.forename: Sohini
authors.initials: S
authors.lastname: Chakraborty
authors.affiliation: Division of Molecular Medicine, Bose Institute, Kolkata, West Bengal 700054, India.
authors.forename: Shibjyoti
authors.initials: S
authors.lastname: Debnath
authors.affiliation: Wipro GE Healthcare, Kolkata, India.
authors.forename: Sougata Sinha
authors.initials: SS
authors.lastname: Ray
authors.affiliation: The Bioinformatics Center, Bose Institute, Kolkata, West Bengal 700054, India.
authors.forename: Zhumur
authors.initials: Z
authors.lastname: Ghosh
authors.affiliation: Division of Molecular Medicine, Bose Institute, Kolkata, West Bengal 700054, India. Electronic address: kbiswas_1@yahoo.com.
authors.forename: Kaushik
authors.initials: K
authors.lastname: Biswas
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism; D005678:G(M2) Ganglioside / Q000378:metabolism* / Q000494:pharmacology; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D047468:Immunoprecipitation; D019012:Integrin beta1 / Q000378:metabolism*; D007700:Kinetics; D018613:Microscopy, Confocal; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D011485:Protein Binding; D025941:Protein Interaction Mapping; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D020349:Surface Plasmon Resonance; D013997:Time Factors; D014162:Transfection; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D019012:Integrin beta1; D005678:G(M2) Ganglioside; D017350:N-Acetylgalactosaminyltransferases; C023220:(N-acetylneuraminyl)-galactosylglucosylceramide N-acetylgalactosaminyltransferase; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Ganglioside; MAP kinases; Microarray; RNAi; Tumor cell migration; Tumor cell proliferation, integrin