Abstract

Our studies supported by grant R01 CA80054 have revealed the presence of membrane microdomains that control carbohydrate-dependent or carbohydrate-modulated cell adhesion coupled with signal transduction, termed """"""""glycosynapses"""""""" (Glysyn). Structure and function of Glysyn are correlated closely with cell growth control and invasive/ metastatic properties of certain tumor cells: (i) Glysyn 1 consists of GM3, growth factor receptor, CD9 or CD81, Src family kinase, and its physiological inhibitor Csk. Its function in transformed cells is associated with loss of growth control (contact inhibition), (ii) Glysyn 3 consists of N-glycosylated integrin and tetraspanin (TSP) complexed with ganglioside (Gg) (particularly GM3), and inhibits integrin-dependent motility, as found originally in IdID cell model and later in various human cancer cell lines. Loss of malignancy, or """"""""reversion"""""""" of oncogenic phenotype, may occur in these cells through increased Glysyn 3. This proposal has two major Specific Aims: 1. Elucidate the growth control mechanism in human normal epithelial cells vs. cancer cell lines, in analogy to previously-studied human lung fibroblast WI38 and oncogenically transformed VA13 cells. Studies are focused on: (a) Glysyn 1 composition as related to growth control, particularly Csk-dependent inhibition of Src kinase; (b) role of TSP CD9-CD81 in Glysyn 1 in facilitating contact inhibition of WI38 vs. its loss in VA13 cells; (c) role of GM3-to-FGFR interaction within the same Glysyn (cis interaction) or between interfacing Glysyn (trans interaction). 2. Elucidate the mechanisms by which Glysyn 3 controls tumor cell invasiveness. Studies are focused on: (a) characterization of components: TSPs, Gg, N-glycosylated integrins; (b) interactions among them; (c) correlation of such interaction with cell motility; (d) effects of Glysyn 3 components on integrin signaling; (e) reversion from malignant to non-malignant phenotype by modification of Glysyn 3 components.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA080054-06A2
Application #
6924228
Study Section
Special Emphasis Panel (ZRG1-PBC (01))
Program Officer
Sussman, Daniel J
Project Start
1999-08-01
Project End
2010-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
6
Fiscal Year
2005
Total Cost
$334,688
Indirect Cost

  Institution

Name
Pacific Northwest Research Institute
Department
Type
DUNS #
041332172
City
Seattle
State
WA
Country
United States
Zip Code
98122

  Publications

Hakomori, Sen-Itiroh; Handa, Kazuko (2015) GM3 and cancer. Glycoconj J 32:1-8
Handa, Kazuko; Hakomori, Sen-Itiroh (2012) Carbohydrate to carbohydrate interaction in development process and cancer progression. Glycoconj J 29:627-37
Ding, Yao; Gelfenbeyn, Kirill; Freire-de-Lima, Leonardo et al. (2012) Induction of epithelial-mesenchymal transition with O-glycosylated oncofetal fibronectin. FEBS Lett 586:1813-20
Freire-de-Lima, Leonardo; Gelfenbeyn, Kirill; Ding, Yao et al. (2011) Involvement of O-glycosylation defining oncofetal fibronectin in epithelial-mesenchymal transition process. Proc Natl Acad Sci U S A 108:17690-5
Guan, Feng; Handa, Kazuko; Hakomori, Sen-Itiroh (2011) Regulation of epidermal growth factor receptor through interaction of ganglioside GM3 with GlcNAc of N-linked glycan of the receptor: demonstration in ldlD cells. Neurochem Res 36:1645-53
Yoon, Seon-Joo; Park, Seung-Yeol; Pang, Poh-Choo et al. (2010) N-glycosylation status of beta-haptoglobin in sera of patients with prostate cancer vs. benign prostate diseases. Int J Oncol 36:193-203
Guan, Feng; Schaffer, Lana; Handa, Kazuko et al. (2010) Functional role of gangliotetraosylceramide in epithelial-to-mesenchymal transition process induced by hypoxia and by TGF-{beta}. FASEB J 24:4889-903
Hakomori, Sen-itiroh (2010) Glycosynaptic microdomains controlling tumor cell phenotype through alteration of cell growth, adhesion, and motility. FEBS Lett 584:1901-6
Guan, Feng; Handa, Kazuko; Hakomori, Sen-itiroh (2009) Specific glycosphingolipids mediate epithelial-to-mesenchymal transition of human and mouse epithelial cell lines. Proc Natl Acad Sci U S A 106:7461-6
Park, Seung-Yeol; Yoon, Seon-Joo; Freire-de-Lima, Leonardo et al. (2009) Control of cell motility by interaction of gangliosides, tetraspanins, and epidermal growth factor receptor in A431 versus KB epidermoid tumor cells. Carbohydr Res 344:1479-86

Showing the most recent 10 out of 23 publications