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

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. There is an urgent need to develop novel therapeutic strategy for cancer patient with MDR. Our laboratory recent publications demonstrated that the existence and participation of ABCB1 and the Wnt pathway in drug resistant MES-SA/Dx5 cells that attenuated proteasome inhibitor-induced apoptosis. Furthermore, we are the first discovered that the Wnt5A hypomethylated intron region was detected and abnormal upregulation of Wnt5A and its signaling pathway was shown to contribute to regulating the drug-resistance protein ABCB1 and P-catenin-related genes in antagonizing the toxic effects of doxorubicin in the two MDR cell lines. These results further supported that high correlation between Wnt5A, ABCB1 and VEGF in the 24 clinical chemoresistant breast cancer samples. Moreover, FZD1 regulated PKCS and its signaling transduction pathway plays an important role in drug resistance in MES-SA/Dx5 cells. In addition, recent study also indicated that Wnt5A enhances gene expressions of circulating endothelial progenitor cells via an activation of PKCS, and suggested that PKCS is a key molecule in Wnt5A mediated gene activation. These results suggested that interaction between Wnt5A- and PKCS-related signaling pathway may regulate drug resistant in cancer cells. Taken together, these finding lead us to hypothesize that besides the ABCB1, abnormal activation of Wnt5A signaling pathway might lead to enhance the resistance of cancer to chemotherapy in MDR cell line. Our research proposal has been funded by MOST research grant for 1 year. To test our hypotheses, in this proposal we will continue to focus on the following specific aims: (1) To investigate the Wnt5A/Frizzled signaling modulates the drug resistance of multidrug resistant cancer cells, (2) To study whether DNA demethylation contributes to altered expression of Wnt5A in parental cancer cells during long-term doxorubicin treatment, and (3) To validate Wnt5A and its related signaling pathway in clinical significance of multiple drug resistant cancers by using large scale of clinical samples. 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:PC10408-1252
External Project ID:MOST104-2320-B182-020-MY3