Development and progression of multiple myeloma is dependent on the bone marrow (BM) microenvironment, and within the BM, a number of factors are secreted, including the Wnt ligands. Bone marrow stromal cells (BMSC) secrete Wnt ligands that activate Wnt signaling in multiple myeloma. The canonical Wnt pathway which is, mediated through the transcriptional effector β-catenin (β-cat) is commonly deregulated in many cancers. Cells with active β-cat-regulated transcription (CRT) are protected against apoptosis; conversely inhibition of CRT may prevent cell proliferation.
Materials and Methods
In this study, we tested the efficacy of recently described inhibitors of CRT (iCRTs; oxazole and thiazole) for their selective antagonistic effect on Wnt-β-cat response in MM cells MM1, U266, BMSC and primary BMMC obtained from patient samples (n=16).
We demonstrate that iCRTs we used block Wnt/β-cat reporter activity, down regulate β-cat expression and inhibit cell proliferation in a dose dependent manner with an optimal dose closer to 15 µM. Our data further indicate that iCRTs do not influence the expression of the upstream components of the Wnt pathway DKK1 at the optimal dose, suggesting that iCRTs may specifically target β-cat in MM cells. Additionally, iCRT-treatment of MM cells co-cultured with BMSC showed an inhibitory effect on VEGF and cell migration.
This study provides the first in vitro data evaluation of newly described iCRTs as potential Wnt-β-cat/VEGF pathway antagonists in multiple myeloma.