Dissecting Role of the Wnt5A in Multiple Drug Resistant Cancer Cells and Its Clinical Significance

Multiple drug resistance (MDR) is a major issue to attenuate the effectiveness of chemotherapy to many human malignancies. Despite MDR inhibitors been discovered for many years, but the severe side effects were discovered. Our previous study demonstrated that compared to the parental human uterus sarcoma cell line MES-SA cells, MES-SA/Dx5 cells highly expressed the P-glycoprotein was more resistant to the doxorubicin-induced apoptosis. The existence and participation of P-glycoprotein and the Wnt pathway in an MDR cell line that attenuated proteasome inhibitor-induced apoptosis. Furthermore, from cDNA expression array and methylation array data, we identified two candidate proteins, Wingless-type MMTV integration site family, member 5A (Wnt5A) and PKCδ, had lower methylation status and higher expression level in the MDR cell line. Moreover, we also demonstrated that PKCδ signaling transduction pathway play an important role in drug resistance in MDR cell line. Since Wnt5A expression was highly related to cancer progression in different kinds of tumors and the PKCδ expression was highly related to cancer abnormal physiology including metastasis and drug-resistance. In addition, recent study also indicated that Wnt5A enhances gene expressions of circulating endothelial progenitor cells via an activation of PKCδ, and suggested that PKCδ is a key molecule in Wnt5A mediated gene activation. Taken together, these finding lead us to hypothesize that besides the P-glycoprotein, abnormal activation of Wnt5A signaling pathway might lead to enhance the resistance of cancer to chemotherapy in MDR cell line. To test our hypotheses, we will focus on the following specific aims: (1) To verify the role of Wnt5A in drug-resistant in two multidrug resistant cancer cells, (2) To investigate the Wnt 5a/frizzled signalling modulates the drug resistance of multidrug resistant cancer cells, and (3) To validate Wnt5A and related signal pathway in clinical significance of multiple drug resistant cancers. We anticipate to completing this proposed project within three years. Preliminary studies have generated exciting data to support our hypothesis. We believe that this study not only can improve our understanding the role of Wnt5A in MDR cells and its clinical significance but also will lead us to develop a new strategy for treatment of multiple drug resistance cancer in near future.

Project ID:PC10308-1712
External Project ID:MOST103-2320-B182-021