Analysis of Pro-Apoptotic and Antiangiogenic Activity of CC3 in Breast Cancer Cells

摘要

CC3 was identified as a metastasis suppressor protein in vivo. This laboratory demonstrated that CC3 impairs apoptotic resistance of cells derived from aggressive tumors and inhibits production of angiogenic factors by these cells. CC3 expression was introduced into two breast carcinoma cell lines derived from metastatic tumors and expressing very low levels of this protein. Expression of exogenous CC3 lead to enhancement of their apoptotic responses to growth factors withdrawal and treatment with cytotoxic drugs. However, there was no effect of CC3 expression on angiogenic activity of breast cancer cells which was very low even prior to introduction of CC3. To understand the mechanisms of the pro-apoptotic activity of CC3, we have conducted analysis of cellular proteins that interact with CC3. Mass-spectormetric analysis identified five importins beta and one exporting, i.e. proteins that serve as nuclear transport receptors. We have analyzed the possible role of CC3 in regulation of nuclear import of proteins. Importantly, by using specific mutants of CC3, we have shown that the inhibitory activity of CC3 in nuclear import is tightly linked to its ability to induce apoptosis. We suggest that CC3 inhibits nuclear import under conditions of stress leading to apoptosis and present data that in breast cancer cells high levels of CC3 could impair survival in response to stress.