GD3 Synthase Expression Enhances Proliferation and Tumor Growth of MDA-MB-231 Breast Cancer Cells through c-Met Activation

Abstract

The disialoganglioside G D3 is overexpressed in ∼50% of invasive ductal breast carcinoma, and the G D3 synthase gene (ST8SIA1) displays higher expression among estrogen receptor-negative breast cancer tumors, associated with a decreased overall survival of breast cancer patients. However, no relationship between ganglioside expression and breast cancer development and aggressiveness has been reported. We have previously shown that overexpression of G D3 synthase induces the accumulation of b-and c-series gangliosides (G D3 , G D2 , and G T3 ) at the cell surface of MDA-MB-231 breast cancer cells together with the acquisition of a proliferative phenotype in the absence of serum. Here, we show that phosphoinositide 3-kinase/Akt and mitogen-activated protein kinase/extracellular signal-regulated kinase pathways are constitutively activated in G D3 synthaseexpressing cells. Analysis of phosphorylation of tyrosine kinase receptors shows a specific c-Met constitutive activation in G D3 synthase-expressing cells, in the absence of its ligand, hepatocyte growth factor/scatter factor. In addition, inhibition of c-Met or downstream signaling pathways reverses the proliferative phenotype. We also show that G D3 synthase expression enhances tumor growth in severe combined immunodeficient mice. Finally, a higher expression of ST8SIA1 and MET in the basal subtype of human breast tumors are observed. Altogether, our results show that G D3 synthase expression is sufficient to enhance the tumorigenicity of MDA-MB-231 breast cancer cells through a ganglioside-dependent activation of the c-Met receptor.

Glycolipid GD3 and GD3 synthase are key drivers for glioblastoma stem cells and tumorigenicity

“…Recently, clinical studies showed that high expression of GD3S was found in estrogen receptor (ER)-negative breast cancer and was associated with poor histological grade in ER-negative tumors (29). GD3S can enhance proliferation of MDA-MB-231 breast cancer cells through the constitutive activation of the c-MET receptor and downstream mitogen-activated protein kinase/extracellular signal-regulated kinase and phosphoinositide-3 kinase/Akt signaling pathways (35). With respect to breast CSCs, GD3S not only regulates epithelial-mesenchymal transition and CSC properties but also metastasis in vivo (46).…”

Targeting of tumor-associated gangliosides with antibodies affects signaling pathways and leads to cell death including apoptosis

“…Cazet et al reported that over-expression of the GD3 synthase in a clone of breast cancer cell line MDA-MB-231 was correlated with high proliferation rate in the absence of serum or exogenous growth factors, activation of c-MET that was independent of HGF-binding, activation of PI3K/ AKT and ERK signaling, and tumor growth in a SCID mouse model [52]. Moreover, the anti-GD2 4G2 mAbtreatment of the cells reduced their viability and this was correlated with decreased phosphorylation of c-MET.…”

Apoptosis of Breast Cancer Cells: Modulation of Genes for Glycoconjugate Biosynthesis and Targeted Drug Delivery

“…16.3 ) (Basu et al 2004a ) occurs in those cell lines at much higher concentrations (50-150 m M) (Boyle et al 2006 ) by EBRAP followed by activation of caspase-8 ( Fig. 16.3 ) Several new chemicals have been tested in recent years for induction of the apoptotic process by activating IMCAP (internal mitochondrial caspase activating pathway), NF-kappaB (NFKBAP), EBRAP (external Bad-receptor activating pathway), or CPKAP pathway (Yuan et al 2011 ;Leung et al 2011 ;Ullah et al 2011 ;Marchetti et al 2011 ;Kim et al 2010 ;Laezza et al 2010 ;Wesierska et al 2011 ;Chou et al 2010 ;Zhang et al 2010 ;Patil et al 2010 ;Banerjee et al 2010 ;Shirure et al 2011 ;Cazet et al 2010 ) . We also tested activation of apoptosis via all other pathways given in Table 16.1 in the above mentioned cell lines using those apoptotic agents ( Fig.…”

“…Targeting mitochondria as a cancer therapeutic strategy is of interest in recent years. Besides recognition of inhibitors of GSL biosynthesis ( l -PPMP, d -PPMNP, and d -PDMP) and DNA biosynthesis (cisplatin) in our laboratory (Basu et al 2004a, b, c ;Ma et al 2004 ;Boyle et al 2006 ) several other different chemicals have been tested as apoptosis inducing agents (via intrinsic mitochondrial or extrinsic receptor pathways) in breast cancer cells Patil et al 2010 ;Banerjee et al 2010Banerjee et al , 2011Shirure et al 2011 ;Cazet et al 2010 ;Jada et al 2008 ;Domingo-Domenech et al 2008 ;Nakagawa et al 2007 ;Nakajima et al 2007 ;Sato-Cerrato et al 2005 ;Balabhadrapatharuni et al 2005 ;Hatasukari et al 2003 ;Chung et al 2002 ;Hansen et al 2000 ;Fromigue et al 2003 ;Elton et al 2000 ;Distefano et al 1998 ;Han et al 1998 ;Schwartz et al 1997 ;Sarkar et al 2007 ;Singh et al 2009 ;Lu et al 2006 ;Somers-Edgar and Rosegren 2009 ;Neuzil et al 2007 ;Fulda et al 1997 ;Li et al 2010a ;Chaouki et al 2010 a;Mullauer et al 2011a ;Kessler et al 2007a ;Laszczyk 2009 ;Bzesk et al 2006a ;Goldoni et al 2008 a;Ellerby et al 1999 ) .…”