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.