Role of the Cadherin-11/Rac1/Stat3 Axis in Src-Mediated Transformation and in Adipocytic Differentiation
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Authors
Guy, Stephanie
Date
Type
thesis
Language
eng
Keyword
Stat3 , Src transformation , Adipocytic differentiation , Cadherin-11 , Rac1
Alternative Title
Abstract
Stat3 (signal transducer and activator of transcription-3) is activated by phosphorylation on tyrosine-705 (Stat3-ptyr705) downstream of cytokines, growth factors, and oncogenes. Our lab has demonstrated that engagement of cadherins, a calcium-dependent family of cell-cell adhesion receptors, can also activate Stat3 via upregulation of the Rac1 and Cdc42 small GTPases and IL6 family cytokines, resulting in increased expression of genes involved in cell division and survival.
Oncogenes such as Src have been shown to negatively regulate the epithelial (E)-cadherin through a number of different mechanisms. Results presented in this thesis reveal, for the first time, that activated Src can also negatively affect levels of the mesenchymal cadherin-11 (Cad11), which is associated with metastasis in cancers such as breast and prostate. Indeed, stable expression of different levels of activated Src showed an inverse correlation between Src and Cad11 protein levels. Interestingly, cells expressing the highest Src levels had no Cad11 and low levels of Stat3-ptyr705, and Stat3-ptyr705 levels did not increase in Cad11-knockdown cells in which activated Src was expressed, suggesting that Src requires Cad11 to activate Stat3. Most importantly, we report that Src-expressing cells deficient in Cad11 succumb to apoptosis at high densities, pointing to a significant role of the Cad11/Stat3 axis in tumour cell survival signalling.
Stat3 activation at confluence was also shown to be important for adipocytic differentiation. Inhibition of Stat3 at the onset of differentiation dramatically reduced the levels of adipocyte protein 2 (aP2) and lipid accumulation, while inhibition of Stat3 after several days of differentiation had no effect. Inhibition of Rac1, an effector of Cad11, was also shown to reduce aP2 and lipid levels, and activated Rac promoted early expression of aP2. Taken together, our results suggest that the survival signal initiated by cadherin engagement is critical for both differentiation and neoplastic transformation. It is especially critical for the survival of tumour cells, which may be overly dependent upon constitutively activated Stat3. Inhibition of Cad11 in cancer therapy would promote apoptosis of metastatic cells specifically (through Stat3 inactivation), a finding which could have important therapeutic implications.
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ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.