Ganglioside GD3 Enhances Invasiveness of Gliomas by Forming a Complex with Platelet-derived Growth Factor Receptor α and Yes Kinase

Ohkawa, Yuki; Momota, Hiroyuki; Kato, Akira; Hashimoto, Noboru; Tsuda, Yusuke; Kotani, Norihiro; Honke, Koichi; Suzumura, Akio; Furukawa, Koichi; Ohmi, Yuhsuke; Natsume, Atsushi; Wakabayashi, Toshihiko

doi:10.1074/jbc.m114.635755

Cited by 73 publications

(58 citation statements)

References 57 publications

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“…GD3 expression also resulted in the enhanced cell adhesion to various extracellular matrices (17). Involvement of increased phosphorylation of a Src kinase family, Yes, due to GD3, was also demonstrated in melanomas (18) and in gliomas (34).…”

Section: Discussionmentioning

confidence: 89%

Neogenin, Defined as a GD3-associated Molecule by Enzyme-mediated Activation of Radical Sources, Confers Malignant Properties via Intracytoplasmic Domain in Melanoma Cells

Kaneko

Ohkawa

Hashimoto

et al. 2016

Journal of Biological Chemistry

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To investigate mechanisms for increased malignant properties in malignant melanomas by ganglioside GD3, enzymemediated activation of radical sources and subsequent mass spectrometry were performed using an anti-GD3 antibody and GD3-positive (GD3؉) and GD3-negative (GD3-) melanoma cell lines. Neogenin, defined as a GD3-neighbored molecule, was largely localized in lipid/rafts in GD3؉ cells. Silencing of neogenin resulted in the reduction of cell growth and invasion activity. Physical association between GD3 and neogenin was demonstrated by immunoblotting of the immunoprecipitates with anti-neogenin antibody from GD3؉ cell lysates. The intracytoplasmic domain of neogenin (Ne-ICD) was detected in GD3؉ cells at higher levels than in GD3؊ cells when cells were treated by a proteasome inhibitor but not when simultaneously treated with a ␥-secretase inhibitor. Exogenous GD3 also induced increased Ne-ICD in GD3؊ cells. Overexpression of Ne-ICD in GD3؊ cells resulted in the increased cell growth and invasion activity, suggesting that Ne-ICD plays a role as a transcriptional factor to drive malignant properties of melanomas after cleavage with ␥-secretase. ␥-Secretase was found in lipid/rafts in GD3؉ cells. Accordingly, immunocyto-staining revealed that GD3, neogenin, and ␥-secretase were co-localized at the leading edge of GD3؉ cells. All these results suggested that GD3 recruits ␥-secretase to lipid/rafts, allowing efficient cleavage of neogenin. ChIP-sequencing was performed to identify candidates of target genes of Ne-ICD. Some of them actually showed increased expression after expression of Ne-ICD, probably exerting malignant phenotypes of melanomas under GD3 expression.It has been long known that malignant transformation of cells brings about changes in the carbohydrate structures in the glycoproteins and glycolipids expressed on the cell surface (1).In particular, there have been a number of reports on the expression of unique glycosphingolipids in neuroectoderm-derived cancer cells (2), osteosarcomas (3, 4), small lung cancer cells (5, 6), and T-cell leukemia cells (7-9). Some of them have been utilized in the clinical field as tumor markers (10) or target molecules of antibody therapy (11).Because ganglioside GD3 was reported to be neo-antigen in melanomas (12-14), it has attracted the interests of researchers in cancer immunology field, and its expression in normal and cancer tissues has been analyzed (15). The effects of anti-GD3 antibody therapy in melanomas (16) and various aspects of its roles in melanomas have been also reported (17-19). These results suggest that GD3 plays important roles in the enhancement of malignant properties of melanomas (20, 21) by regulating glycolipid-enriched microdomain (GEM) 2 /rafts (22). However, precise mechanisms for GD3 function in cancers have not yet been clarified.To investigate how gangliosides are involved in the regulation of cell signaling, we have applied enzyme-mediated activation of radical sources (EMARS) method (23) to identify membrane molecules interacting wi...

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Section: Discussionmentioning

confidence: 89%

Neogenin, Defined as a GD3-associated Molecule by Enzyme-mediated Activation of Radical Sources, Confers Malignant Properties via Intracytoplasmic Domain in Melanoma Cells

Kaneko

Ohkawa

Hashimoto

et al. 2016

Journal of Biological Chemistry

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“…Therefore, the new potential biomarker for early diagnosis and novel therapeutic target needs to be explored. Although dozens of studies have indicated the complex gene interaction and molecular modulation network in the development of glioma, the research on revealing the oncogenes and tumor suppressors is still on the road [5,6].…”

Section: Introductionmentioning

confidence: 99%

Long noncoding RNA NEAT1 promotes glioma pathogenesis by regulating miR-449b-5p/c-Met axis

et al. 2015

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Growing evidence demonstrates that long noncoding RNAs (lncRNAs) are involved in the progression of various cancers including glioma. Nuclear enriched abundant transcript 1 (NEAT1), an essential lncRNA for the formation of nuclear body paraspeckles, was not fully explored in glioma. We aimed to determine the expression, roles, and functional mechanisms of NEAT1 in the progression of glioma. By real-time PCR, we suggested that NEAT1 was upregulated in glioma tissues than noncancerous brain tissues. Knockdown of NEAT1 reduced glioma cell proliferation, invasion, and migration. RNA immunoprecipitation assay combined with luciferase reporter assay confirmed miR-449b-5p-specific binding to NEAT1. Furthermore, we verified that c-Met was a directly target of miR-449b-5p. Rescue assays demonstrated NEAT1 functions a molecular sponge for miR-449b-5p and leads to the upregulation of c-Met. This regulation menchaism promotes glioma pathogenesis and may provide a potential target for the prognosis and treatment of glioma.

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“…C‐2, C‐6, and C‐8 are GD2 − SK‐LC‐17 transfectants (Figures A, ). Tumor‐specific gangliosides coordinately work with plasma membrane proteins in cancer cells, which leads to enhancement of malignant phenotypes . However, it is not well known what kind of plasma membrane proteins work together with GD2 in SCLC cells.…”

Section: Resultsmentioning

confidence: 99%

“…Although roles of GD2 in malignant phenotypes of SCLC have been analyzed, there is no information about molecules interacting with GD2 in GEM/rafts. To date, it has been reported that GD3 interacts with membrane proteins in melanomas and glioma cells, which promotes malignant phenotypes of individual cancer cells . In this study, we aimed to reveal the molecular mechanisms by which GD2 expressed on the membrane of SCLC cells induces malignant phenotypes, then used EMARS combined with MS to address this aim.…”

Section: Introductionmentioning

confidence: 99%

ASC amino acid transporter 2, defined by enzyme‐mediated activation of radical sources, enhances malignancy of GD2‐positive small‐cell lung cancer

et al. 2018

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Ganglioside GD2 is specifically expressed in small‐cell lung cancer (SCLC) cells, leading to enhancement of malignant phenotypes, such as cell proliferation and migration. However, how GD2 promotes malignant phenotypes in SCLC cells is not well known. In this study, to reveal the mechanisms by which GD2 increases malignant phenotypes in SCLC cells, we used enzyme‐mediated activation of radical sources combined with mass spectrometry in GD2+ SCLC cells. Consequently, we identified ASC amino acid transporter 2 (ASCT2), a major glutamine transporter, which coordinately works with GD2. We showed that ASCT2 was highly expressed in glycolipid‐enriched microdomain/rafts in GD2+ SCLC cells, and colocalized with GD2 in both proximity ligation assay and immunocytostaining, and bound with GD2 in immunoprecipitation/TLC immunostaining. Malignant phenotypes of GD2+ SCLC cells were enhanced by glutamine uptake, and were suppressed by L‐γ‐glutamyl‐p‐nitroanilide, a specific inhibitor of ASCT2, through reduced phosphorylation of p70 S6K1 and S6. These results suggested that ASCT2 enhances glutamine uptake in glycolipid‐enriched microdomain/rafts in GD2+ SCLC cells, leading to the enhancement of cell proliferation and migration through increased phosphorylation of the mTOR complex 1 signaling axis.

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Ganglioside GD3 Enhances Invasiveness of Gliomas by Forming a Complex with Platelet-derived Growth Factor Receptor α and Yes Kinase

Cited by 73 publications

References 57 publications

Neogenin, Defined as a GD3-associated Molecule by Enzyme-mediated Activation of Radical Sources, Confers Malignant Properties via Intracytoplasmic Domain in Melanoma Cells

Neogenin, Defined as a GD3-associated Molecule by Enzyme-mediated Activation of Radical Sources, Confers Malignant Properties via Intracytoplasmic Domain in Melanoma Cells

Long noncoding RNA NEAT1 promotes glioma pathogenesis by regulating miR-449b-5p/c-Met axis

ASC amino acid transporter 2, defined by enzyme‐mediated activation of radical sources, enhances malignancy of GD2‐positive small‐cell lung cancer

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