Reversion of the Jun-induced oncogenic phenotype by enhanced synthesis of sialosyllactosylceramide (GM3 ganglioside)

Miura, Yutaka; Kainuma, Mami; Jiang, Hao; Velasco, Hershey; Vogt, Peter K.; Hakomori, Sen‐itiroh

doi:10.1073/pnas.0407297101

Cited by 69 publications

(51 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although we do not know at present the mechanism of the GM3 synthase activation by NEU3 silencing that seems contradictory from a physiological point of view, GM3 synthase activation would be necessary for apoptosis induction. In this context, our results are consistent with those by other investigators that GM3 synthase is upregulated during cell apoptosis (Sohn et al, 2006;Valaperta et al, 2006) and downregulated in malignant transformation (Watanabe et al, 2002;Miura et al, 2004). GM3 synthase activation in our experiments, however, occurred in cancer cell death, and in neuronal cell death in the report of Sohn et al (2006).…”

Section: Discussionsupporting

confidence: 82%

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

et al. 2007

View full text Add to dashboard Cite

Section: Discussionsupporting

confidence: 82%

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

et al. 2007

View full text Add to dashboard Cite

“…Thus, various cell adhesion processes mediated by GSLs and TSP cause extensive phenotypic changes, including reversion from malignant to normal cell phenotype (8,9,25). In analogy, Bissell and colleagues (26,27) showed that functional antibodies directed to ␤1 integrin of breast cancer cells caused reversion, in vitro and in vivo, to normal cellular organization, indicating that malignancy may arise from disorganization of glycosynaptic microdomain rather than from changes in gene structure and expression.…”

Section: Discussionmentioning

confidence: 99%

Ganglioside GM2/GM3 complex affixed on silica nanospheres strongly inhibits cell motility through CD82/cMet-mediated pathway

Todeschini

Santos

Handa

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

115

View full text Add to dashboard Cite

Ganglioside GM2 complexed with tetraspanin CD82 in glycosynaptic microdomain of HCV29 and other epithelial cells inhibits hepatocyte growth factor-induced cMet tyrosine kinase. In addition, adhesion of HCV29 cells to extracellular matrix proteins also activates cMet kinase through ''cross-talk '' of integrins with cMet, leading to inhibition of cell motility and growth. Present studies indicate that cell motility and growth are greatly influenced by expression of GM2, GM3, or GM2/GM3 complexes, which affect cMet kinase activity of various types of cells, based on the following series of observations: (i) Cells expressing CD82, cultured with GM2 and GM3 cocoated on silica nanospheres, displayed stronger and more consistent motility inhibition than those cultured with GM2 or GM3 alone or with other glycosphingolipids. (ii) GM2-GM3, in the presence of Ca 2؉ form a heterodimer, as evidenced by electrospray ionization (ESI) mass spectrometry and by specific reactivity with mAb 8E11, directed to GM2/GM3 dimer structure. (iii) Cells expressing cMet and CD82 were characterized by enhanced motility associated with HGF-induced cMet activation. Both cMet and motility were strongly inhibited by culturing cells with GM2/GM3 dimer coated on nanospheres. (iv) Adhesion of HCV29 or YTS-1/CD82 cells to laminin-5-coated plate activated cMet kinase in the absence of HGF, whereas GM2/GM3 dimer inhibited adhesioninduced cMet kinase activity and inhibited cell motility. (v) Inhibited cell motility as in i, iii, and iv was restored to normal level by addition of mAb 8E11, which blocks interaction of GM2/GM3 dimer with CD82. Signaling through Src and MAP kinases is activated or inhibited in close association with cMet kinase, in response to GM2/GM3 dimer interaction with CD82. Thus, a previously uncharacterized GM2/GM3 heterodimer complexed with CD82 inhibits cell motility through CD82-cMet or integrin-cMet pathway.glycosphingolipid ͉ growth factor receptor ͉ ldlD cells ͉ tyrosine kinase G lycosphingolipids (GSLs), including gangliosides, interact with specific membrane proteins, such as growth factor receptors, integrins, tetraspanins (TSPs), and nonreceptor cytoplasmic kinases (e.g., Src family kinases and small G proteins), to form glycosynaptic microdomains controlling GSL-dependent or -modulated cell adhesion, growth, and motility (for review, see refs. 1-3).Our previous studies indicate the following: (i) Ganglioside the GM3/TSP CD9 complex interacts with integrin ␣3␤1 or ␣5␤1 and inhibits motility of CD9-expressing tumor cells (4, 5). (ii) The GM3/CD9/CD81 complex inhibits tyrosine kinase associated with fibroblast growth factor receptor (FGFR) (6) and blocks functional interaction of integrins with FGFR (7). (iii) Enhancement of GM3 or CD9 level in bladder cancer cell line YTS-1 causes reversion to normal phenotype, whereby Src kinase activity is strongly inhibited (8).In contrast to these previous studies, focused on GM3-CD9 interaction that inhibits tumor cell motility, our recent studies (9) addressed the functional role of t...

show abstract

“…There is increasing evidence that GSLs and glycosylation status of proteins play key roles in defining ontogenic development (12)(13)(14)(15), oncogenic transformation (26,27), and their phenotypic reversion (28,29). GSLs and protein glycosylation are therefore expected to play some role in EMT process.…”

Section: Discussionmentioning

confidence: 99%

Specific glycosphingolipids mediate epithelial-to-mesenchymal transition of human and mouse epithelial cell lines

Guan

Handa

Hakomori

2009

Proc. Natl. Acad. Sci. U.S.A.

117

123

View full text Add to dashboard Cite

Epithelial-to-mesenchymal cell transition (EMT) is a basic process in embryonic development and cancer progression. The present study demonstrates involvement of glycosphingolipids (GSLs) in the EMT process by using normal murine mammary gland NMuMG, human normal bladder HCV29, and human mammary carcinoma MCF7 cells. Treatment of these cells with D-threo-1-(3 ,4 -ethylenedioxy)-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol (EtDO-P4), the glucosylceramide (GlcCer) synthase inhibitor, which depletes all GSLs derived from GlcCer, (i) down-regulated expression of a major epithelial cell marker, E-cadherin; (ii) up-regulated expression of mesenchymal cell markers vimentin, fibronectin, and N-cadherin; (iii) enhanced haptotactic cell motility; and (iv) converted epithelial to fibroblastic morphology. These changes also were induced in these cell lines with TGF-␤, which is a well-documented EMT inducer. A close association between specific GSL changes and EMT processes induced by EtDO-P4 or TGF-␤ is indicated by the following findings: (i) The enhanced cell motility of EtDO-P4-treated cells was abrogated by exogenous addition of GM2 or Gg4, but not GM1 or GM3, in all 3 cell lines. (ii) TGF-␤ treatment caused changes in the GSL composition of cells. Notably, Gg4 or GM2 was depleted or reduced in NMuMG, and GM2 was reduced in HCV29. (iii) Exogenous addition of Gg4 inhibited TGF-␤-induced changes of morphology, motility, and levels of epithelial and mesenchymal markers. These observations indicate that specific GSLs play key roles in defining phenotypes associated with EMT and its reverse process (i.e., mesenchymal-to-epithelial transition).E-cadherin ͉ EtDO-P4 ͉ Gg4 ͉ motility ͉ TGF-beta E pithelial cells in tissues or cultured in vitro change their morphology, growth behavior, and motility when they encounter a different microenvironment. For example, epithelial cells that come in contact with soluble extracellular matrix components acquire characteristics similar to those of mesenchymal fibroblasts, as originally observed by Hay and colleagues (1-3). After extensive further studies, a concept emerged that the transitional process from epithelial to mesenchymal phenotype is commonly associated with embryonic development, as well as pathological conditions, such as fibrosis or cancer metastasis, and the process was termed ''epithelial-to-mesenchymal transition'' (EMT) (4-10).The EMT process has been characterized, in addition to cell morphology change and increased cell motility, by a striking decline in epithelial markers, such as E-cadherin, desmoplakin, and cytokeratins, accompanied by enhanced expression of mesenchymal markers, such as vimentin, fibronectin, and N-cadherin (10, 11).Previous studies from our group and others have demonstrated that glycosphingolipids (GSLs) mediate cell adhesion (12-15), and they modulate cell growth through their effect on growth factor receptor tyrosine kinases (16)(17)(18)(19)(20). In addition, we have demonstrated that some GSLs, particularly gangliosides, play an essential role...

show abstract

Reversion of the Jun-induced oncogenic phenotype by enhanced synthesis of sialosyllactosylceramide (GM3 ganglioside)

Abstract: ganglioside-enriched microdomain ͉ tetraspanin ͉ integrin ͉ anchorage-independent

Cited by 69 publications

References 37 publications

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

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

Ganglioside GM2/GM3 complex affixed on silica nanospheres strongly inhibits cell motility through CD82/cMet-mediated pathway

Specific glycosphingolipids mediate epithelial-to-mesenchymal transition of human and mouse epithelial cell lines

Contact Info

Product

Resources

About