Selective abrogation of the proinvasive activity of the trefoil peptides pS2 and spasmolytic polypeptide by disruption of the EGF receptor signaling pathways in kidney and colonic cancer cells

Abstract

Trefoil peptides (TFFs) are now considered as scatter factors, proinvasive and angiogenic agents acting through cyclooxygenase-2 (COX-2)-and thromboxane A2 receptor (TXA2-R)-dependent signaling pathways. As expression and activation levels of the epidermal growth factor receptor (EGFR) predict the metastatic potential of human colorectal cancers, the purpose of this study was to establish whether the EGF receptor tyrosine kinase (EGFR-TK) contributes to cellular invasion induced by TFFs in kidney and colonic cancer cells. Both the dominant negative form of the EGFR (HER-CD533) and the EGFR-TK inhibitor ZD1839 (Iressa) abrogated cellular invasion induced by pS2, spasmolytic polypeptide (SP) and the src oncogene, but not by ITF and the TXA2-R. Similarly, EGFR-TK inhibition by ZD1839 reversed the invasive phenotype promoted by the constitutively activated form of the EGFR (EGFRvIII) and the EGFR agonists transforming growth factor alpha (TGFa), amphiregulin and EGF. We also provide evidence that TFFs, EGFRvIII, and TGFa trigger common proinvasive pathways using the PI3 0 -kinase and Rho/Rho-kinase cascades. These findings identify the EGFR-TK as a key signaling element for pS2-and SP-mediated cellular invasion. It is concluded that although pS2, SP and ITF belong to the same family of inflammation-and cancerassociated regulatory peptides, they do not control identical signaling networks.

Commutators of PAR-1 signaling in cancer cell invasion reveal an essential role of the Rho–Rho kinase axis and tumor microenvironment

“…In this area, RhoGTPases play pleiotropic roles in cell movements, polarity, vesicle trafficking, and EGF-R processing and degradation, as recently demonstrated for Cdc42 (Cerione, 2004). GPCR controlled by thrombin, bombesin, neurotensin, endothelin, and LPA are also implicated in metalloprotease-mediated EGF-R transactivation (Darmoul et al, 2004;Schafer et al, 2004;Zhao et al, 2004), a major signaling platform in invasive growth (Rodrigues et al, 2003). More recently, the fibroblast-derived matrix metalloprotease MMP-1 in the stromal-tumor microenvironment has been designed as a new PAR-1 activator that promotes invasion and tumorigenesis of breast cancer cells (Boire et al, 2005).…”

Disruption of STAT3 signaling leads to tumor cell invasion through alterations of homotypic cell–cell adhesion complexes

“…Recruitement of the class II PI3-K enzyme is also observed at phosphotyrosine residues Y992, Y1068 and Y1173 on activated EGFR, through the Grb2 adaptor. The majority of these adaptors and associated enzymes are connected with downstream signaling cascades implicated in cellular invasion (Prenzel et al, 2001;Rodrigues et al, 2003). Importantly, these tyrosine residues, including Y992, 1045, 1068, 1086, and 1173, are also functioning as STAT3 docking sites and activation modules through the YXXQ motif present in the EGFR and ErbB3 Cterminus (Hellyer et al, 1998;Xia et al, 2002).…”

“…As shown in Figure 4c, the autonomous invasive potential of the HCT8/S11-STAT3-Y705F cell line is abolished by the PI3-kinase inhibitor LY294002, demonstrating that the catalytic activity of this lipid/ protein kinase is required for the proinvasive impact of STAT3-Y705F. The EGF-R is a scaffold protein that activates and integrates multiple intracellular signaling pathways involved in cellular migration and invasion, including PI3-kinase (Price et al, 1996;Turner et al, 1996;Xie et al, 1998;Yarden, 2001;Rodrigues et al, 2003). The EGF-R tyrosine kinase is frequently overexpressed or constitutively activated in human breast, colon, kidney and prostate tumors.…”

“…of three independent experiments, each performed in triplicate. Significant at *Po0.05 versus control HCT8/S11 cells STAT3 signaling and tumor cell invasion C Rivat et al signaling pathways, including PI3-kinase, the Rho-like GTPases, the ser/thr protein kinases PKC and the EGF-R tyrosine kinase (Kotelevets et al, 1998;Barbier et al, 2001;Rodrigues et al, 2003). We have therefore analysed the functional relationships between these proinvasive signaling elements and the mechanisms underlying the constitutive invasiveness of HCT8/S11 cells stably transfected by the STAT3-Y705F mutant.…”

Trefoil factors: Tumor progression markers and mitogens via EGFR/MAPK activation in cholangiocarcinoma

“…Several ligands of EGFR have been identified [20] , and there is some evidence for the transactivation of EGFR by TFFs. EGFR is a key signaling pathway for TFF1-and TFF2-mediated cellular invasion in kidney and colonic cancer cells [21] , suggesting the capability of TFFs to directly, or indirectly, transactivate the EGFR. While EGFR signaling has been shown to be important in CCA, there has been no report of TFFmediated EGFR pathway activation in CCA.…”