Mouse anti-Human DVL3 monoclonal antibody, clone 5I3

Chemoresistance and recurrence of colorectal cancer are mainly caused by the existence of cancer stem-like cells. Dishevelled-3 (DVL3) is a common member of both Wnt/beta-catenin pathway and the Notch signaling pathway, which were involved in cancer progression, chemoresistance and even maintenance of stem cell-like properties. However, the underlying biological function of DVL3 still remains unclear. In this study, we proposed DVL3 was simultaneously involved in Methotrexate (MTX) resistance and Colorectal cancer (CRC) stemness by bioinformatic analysis. We also demonstrated DVL3 knockdown sensitized CRC cells to MTX and inhibited their stem cell-like properties by functional experiments. As for the mechanism, DVL3 silencing attenuated the activated Notch signaling by down-regulating Notch intracellular domain (NICD) as well as its downstream targets. Additionally, we demonstrated that CRC cancer tissues had greater DVL3 expression than adjacent non-cancer tissues and patients' overall survival was closely associated with DVL3 according to the data in our clinical center. Accordingly, our data suggest that DVL3 is a key regulator in CRC stemness and chemoresistance and targeting DVL3 could be a potential strategy for CRC therapy.

lmatinib-insensitive leukemia stem cells (LSCs) are believed to be responsible for resistance to BCR-ABL tyrosine kinase inhibitors and relapse of chronic myelogenous leukemia (CML). Identifying therapeutic targets to eradicate CML LSCs may be a strategy to cure CML. In the present study, we discovered a positive feedback loop between BCR-ABL and protein arginine methyltransferase 5 (PRMT5) in CML cells. Overexpression of PRMT5 was observed in human CML LSCs. Silencing PRMT5 with shRNA or blocking PRMT5 methyltransferase activity with the small-molecule inhibitor PJ-68 reduced survival, serial replating capacity, and long-term culture-initiating cells (LTC-ICs) in LSCs from CML patients. Further, PRMT5 knockdown or PJ-68 treatment dramatically prolonged survival in a murine model of retroviral BCR-ABL-driven CML and impaired the in vivo self-renewal capacity of transplanted CML LSCs. PJ-68 also inhibited long-term engraftment of human CML CD34(+) cells in immunodeficient mice. Moreover, inhibition of PRMT5 abrogated the Wnt/beta-catenin pathway in CML CD34(+) cells by depleting dishevelled homolog 3 (DVL3). This study suggests that epigenetic methylation modification on histone protein arginine residues is a regulatory mechanism to control self-renewal of LSCs and indicates that PRMT5 may represent a potential therapeutic target against LSCs.