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Plasma membrane-associated sialidase is up-regulated in renal cell carcinoma and promotes interleukin-6-induced apoptosis suppression and cell motility.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2006 Mar 24; Vol. 281 (12), pp. 7756-64. Date of Electronic Publication: 2006 Jan 20. - Publication Year :
- 2006
-
Abstract
- Human plasma membrane-associated sialidase (NEU3), specifically hydrolyzing gangliosides, plays crucial roles in the regulation of cell surface functions. Here we demonstrate that NEU3 mRNA level are increased in renal cell carcinomas (RCCs) compared with adjacent non-tumor tissues, significantly correlating with elevation of interleukin-6 (IL-6), a pleiotropic cytokine that has been implicated in immune responses and pathogenesis of several cancers, including RCCs. In human RCC ACHN cells, IL-6 treatment enhanced NEU3 promoter luciferase activity 2.5-fold and the endogenous sialidase activity significantly. NEU3 transfection or IL-6 treatment resulted in both suppression of apoptosis and promotion of cell motility, and the combination had synergistic effects. NEU3 scarcely affected MAPK- or IL-6-induced STAT3 activation but promoted the phosphatidylinositol 3-kinase (PI3K)/Akt cascade in both IL-6-dependent and -independent ways. Consistent with these data, NEU3 markedly inhibited staurosporine-induced caspase-3 activity and enhanced IL-6-dependent inhibition, which was abolished by LY294002, a PI3K inhibitor. Furthermore, IL-6 promoted Rho activation, and the effect was potentiated by NEU3, leading to increased cell motility that was again affected by LY294002. NEU3 silencing by siRNA resulted in the opposite: decreased Akt phosphorylation and inhibition of Rho activation. Glycolipid analysis showed a decrease in ganglioside GM3 and increase in lactosylceramide after NEU3 transfection, with these lipids apparently affecting cell apoptosis and motility. The results indicate that NEU3 activated by IL-6 exerts IL-6-mediated signaling, largely via the PI3K/Akt cascade, in a positive feedback manner and contributes to expression of a malignant phenotype in RCCs. NEU3 thus may be a useful target for RCC diagnosis and therapy.
- Subjects :
- Apoptosis
Cell Line, Tumor
Cell Movement
Chromatography, Thin Layer
Cytokines metabolism
Enzyme Activation
Enzyme-Linked Immunosorbent Assay
Gene Silencing
Genes, Reporter
Glycolipids chemistry
Humans
Interleukin-6 metabolism
Luciferases metabolism
Models, Genetic
Neuraminidase chemistry
Neuraminidase metabolism
Phenotype
Phosphatidylinositol 3-Kinases metabolism
Phosphorylation
Proto-Oncogene Proteins c-akt metabolism
RNA, Messenger metabolism
RNA, Small Interfering metabolism
Recombinant Proteins chemistry
Reverse Transcriptase Polymerase Chain Reaction
Transfection
Carcinoma, Renal Cell metabolism
Cell Membrane metabolism
Gene Expression Regulation, Neoplastic
Kidney Neoplasms metabolism
Neuraminidase biosynthesis
Up-Regulation
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 281
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 16428383
- Full Text :
- https://doi.org/10.1074/jbc.M509668200