BACKGROUND: 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 de-regulated 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 MM.1, U266, BMSC and primary BMMC obtained from patient samples (n=16). RESULTS: We demonstrated 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. CONCLUSION: This study provides the first in vitro data evaluation of newly-described iCRTs as potential Wnt-β-cat/VEGF pathway antagonists in multiple myeloma.
BACKGROUND: 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 de-regulated 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 MM.1, U266, BMSC and primary BMMC obtained from patient samples (n=16). RESULTS: We demonstrated 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. CONCLUSION: This study provides the first in vitro data evaluation of newly-described iCRTs as potential Wnt-β-cat/VEGF pathway antagonists in multiple myeloma.
Authors: Patrick W B Derksen; Esther Tjin; Helen P Meijer; Melanie D Klok; Harold D MacGillavry; Marinus H J van Oers; Henk M Lokhorst; Andries C Bloem; Hans Clevers; Roel Nusse; Ronald van der Neut; Marcel Spaargaren; Steven T Pals Journal: Proc Natl Acad Sci U S A Date: 2004-04-05 Impact factor: 11.205
Authors: D Ribatti; A Vacca; B Nico; F Quondamatteo; R Ria; M Minischetti; A Marzullo; R Herken; L Roncali; F Dammacco Journal: Br J Cancer Date: 1999-02 Impact factor: 7.640
Authors: Sébastien Foulquier; Evangelos P Daskalopoulos; Gentian Lluri; Kevin C M Hermans; Arjun Deb; W Matthijs Blankesteijn Journal: Pharmacol Rev Date: 2018-01 Impact factor: 25.468
Authors: Joshua D Brown-Clay; Deepika N Shenoy; Olga Timofeeva; Bhaskar V Kallakury; Asit K Nandi; Partha P Banerjee Journal: Oncotarget Date: 2015-06-20