Overcoming Cell Adhesion-Mediated Drug Resistance (Cam-Dr) In Multiple Myeloma By Targeting Possible Crosstalk Between The Thioredoxin System And Mucins

Multiple myeloma (MM) is a clonal plasma B-cell neoplasm that resides in the bone marrow (BM) cavity. While in the BM, the cells interact with BM stromal cells resulting in the secretion of chemokines and growth factors as well as expression of cell adhesion molecules that allow the myeloma cells to migrate to secondary BM sites where they eventually invade and proliferate. These events allow the cells to not only disseminate but also to become chemo-resistant to MM drugs through cell-adhesion mediated drug resistance (CAM-DR). The thioredoxin (Trx) system is one of the major cellular antioxidant systems involved in maintaining redox homeostasis in the cell. Studies have shown that the Trx system system redox-regulates a large number of transcription factors including NF-κβ, p53 and PTEN and is responsible for increased cancer cell proliferation, survival and chemo-resistance. Although inhibition of the Trx system has been shown to re-sensitise bortezomib-resistant MM cells, the effects of its redox activity to overcome CAM-DR remains to be fully elucidated. Mucins are a group of glycoproteins and their functions range from establishing molecular barriers for epithelial surfaces to signal transduction. In addition the mucins are able to mediate cell adhesion properties in cancer cells. Mucins are aberrantly expressed in MM and are also involved in the regulation of ROS. These findings suggest a possibility of crosstalk between the redox systems and mucins that may be involved in the pathogenesis of MM. This project aims to discover the possible crosstalk between the Trx system and mucins with respect to CAM-DR in MM.