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A crucial role of plasma membrane-associated sialidase in the survival of human cancer cells

Oncogene volume 26, pages 2483–2490 (2007)Cite this article

Abstract

Human plasma membrane-associated sialidase (NEU3), a key enzyme for ganglioside degradation, is markedly upregulated in human cancers, leading to apoptosis suppression. To define molecular mechanisms and the possible target for NEU3, its encoding gene was silenced by small interference RNA (siRNA) or overexpressed in human cells. NEU3 siRNA-induced apoptosis with no special stimuli in HeLa cells, accompanied with decreased Bcl-xL and increased mda7 and GM3 synthase mRNA levels, whereas overexpression resulted in the opposite. Carcinoma HT-29 and MCF-7 cells appeared to be similarly affected, but normal cell lines demonstrated no significant changes. NEU3 siRNA was found to inhibit and NEU3 overexpression to stimulate Ras activation with consequent influence on extracellular signal-regulated kinases and Akt. Ras activation by NEU3 was abrogated by PP2 (src inhibitor) or AG1478 (epidermal growth factor receptor (EGFR) inhibitor), and NEU3 actually enhanced EGF-stimulated tyrosine-phosphorylation of EGFR, suggesting that the upstream targets might be tyrosine kinases including src and EGFR, and the subsequent stimulation of Ras cascade leads to the inhibition of cell apoptosis. Glycolipid changes observed seemed to be one of the causes of the cell effects. NEU3 may thus be an essential gene for cancer cell survival and siRNAs targeting this protein could have utility for gene-based therapy of human cancers.

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Abbreviations

Gb3:

globotriaosylceramide

LacCer:

lactosylceramide

mda 7:

melanoma differentiation associated gene-7

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Acknowledgements

This study was supported in part by Grants-in Aid from the Mitsubishi Foundation, and by Grants-in Aid for Scientific Research on Priority Areas Cancer from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Authors and Affiliations

  1. Division of Biochemistry, Miyagi Cancer Center Research Institute, Natori, Miyagi, Japan

    T Wada, K Hata, K Yamaguchi, K Shiozaki, K Koseki, S Moriya & T Miyagi

  2. CREST, JST, Japan

    K Shiozaki, S Moriya & T Miyagi

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  1. T Wada
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  2. K Hata
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  3. K Yamaguchi
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  4. K Shiozaki
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  7. T Miyagi
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Correspondence to T Miyagi.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Wada, T., Hata, K., Yamaguchi, K. et al. A crucial role of plasma membrane-associated sialidase in the survival of human cancer cells. Oncogene 26, 2483–2490 (2007). https://doi.org/10.1038/sj.onc.1210341

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