The Role of Cadherin-11 and gp130 in Transformation by Activated Src

Thumbnail Image
D'Abreo, Carmeline
Cadherin-11, Src, gp130, Stat3
Signal Transducer and Activator of Transcription 3, Stat3, has been associated with cytokine-induced proliferation, anti-apoptosis and neoplastic transformation, while constitutively active Stat3 has been found in many human tumors. Stat3 activation by the Src oncoprotein leads to specific gene regulation and the Stat3 mediated signaling pathway is one of the critical signaling pathways involved in Src oncogenesis. Our laboratory demonstrated that engagement of cadherins, which are a class of cell-cell adhesion molecules, can activate Stat3, even in the absence of direct cell to cell contact. Interestingly, a significant increase in total Rac1 and Cdc42 protein levels triggered by cadherin engagement, and an increase in Rac1 and Cdc42 activity, which led to Stat3 activation by a mechanism involving gp130, a common subunit of the IL-6 family of cytokines, was also observed. To investigate the role of gp130 in vSrc transformation, we knocked down gp130 in vSrc transformed cells and found a decrease in the levels of phosphorylated Stat3, the rate of cell migration, rate of cell proliferation and the anchorage-independent growth. It was also previously demonstrated that vSrc had a negative effect on the function of cadherins. Surprisingly, however, despite the fact that vSrc may reduce cadherin adhesion, previous results in our lab showed that cell density still caused a significant increase in Stat3 activity in vSrc transformed cells. Moreover, Stat3 downregulation induced apoptosis in transformed cells which was more pronounced at high cell densities. This may reflect an increased need for Stat3 activity at high densities, possibly to overcome apoptosis, which raised the question of the actual role of cadherins in the density-mediated activation of Stat3 in such cells. The expression of cadherin-11, a type II cell adhesion molecule, is associated with invasive breast cancer and many studies suggest that it may play a significant role in facilitating tumor cell invasion and the formation of metastatic tumors. Since Src and its family members participate in many aspects of tumor progression and metastasis, it was interesting to see if Src needed cadherin-11 for neoplastic transformation. To this effect, when we knocked down cadherin-11 in Balb/c3T3 cells, we observed a significant reduction in levels of phosphorylated Stat3-ptyr705 which was also observed when vSrc was expressed in them. Moreover, expressing vSrc in cells in which cadherin-11 was knocked down also decreased the anchorage –independent growth and increased apoptosis indicating that cadherin-11 is needed for transformation and survival respectively, in vSrc transformed cells. Our results thus demonstrate that cadherin-11 may be a good target for the selective elimination of cells expressing Src and presumably other oncogenes as well. Stat3 activation by cadherins is so potent and important that tumor cell death can be enhanced by cadherin inhibition. In our experiments, the inhibition of cadherin-11 induced apoptosis in Src expressing cells, while the normal cells were not affected. Elucidation of the functions and regulation of cadherin-11 may enhance our understanding of the roles of cadherins in invasive cancer and may provide future targets for therapy. Through our work, the cadherin/IL-6 pathway may emerge as a crucial Stat3 activator in vSrc expressing cells.
External DOI