Versican G3 Modulates Breast Cancer Cell Apoptosis enhanced effects on cell apoptosis was blocked by AG 1478 and SP 600125 but was not appreciably by PD 98059. This supports versican G3 promotion of tumor cell apoptosis induced by C2- ceramide and Docetaxel occurring through EGFR/JNK mediated signaling. Persistently high levels of p-SAPK/JNK observed in G3- expressing breast cancer cells resulted in an increase of one of the Figure 8. Versican G3 domain modulates breast cancer cell apoptosis in response to chemotherapy and EGFR targeting therapy. a) A model of versican G3 in modulating breast cancer cell apoptosis in chemotherapy and EGFR targeting therapy. The differential responses to chemical induced apoptosis depend on activation and balance of EGFR signaling and its further enhanced down stream pathway. Overexpressing of versican G3 in breast cancer cell enhances expression of EGFR signal and its downpathways. Usually it will process to ERK and GSK pathway, which expresses enhanced cell survival. The GSK works as a key point, which inhibits expression of JNK and makes the cell process to the ERK pathway. Expression of JNK may induce cell apoptosis. Some chemicals like c2-ceramide and Docetaxel can directly inhibit expression of GSK, which alleviates its inhibition on JNK pathway. Expression of JNK can also inhibit expression of GSK, making the G3 expression cells process to apoptosis. b) Vector and G3 transfected 66c14 cells (16106) were inoculated and cultured in 10% FBS/DMEM medium in 6 well culture dishes for 12 hours. After cell attachment, cells were treated with serum free DMEM medium for 4 days or treated with 40 mM C2-ceramide, 2 mM Docetaxel, 8 mM Doxorubicin, or 10 mM Epirubicin for 2 hours. Cell lysates prepared were subjected to immunoblotting with antibodies to pERK, GSK-3b (S9P), pSAPK/JNK and b-actin. doi:10.1371/journal.pone.0026396.g008 PLoS ONE | www.plosone.org 12 November 2011 | Volume 6 | Issue 11 | e26396