Targeting the β-catenin/TCF transcriptional complex in the treatment of multiple myeloma
| Autor: | Kumar Sukhdeo, Yunyu Zhang, Mei Zheng, Melissa Rooney, Haiying He, Daniel R. Carrasco, Jui Dutta, Daniel E. Carrasco, Constantine S. Mitsiades, Kenneth C. Anderson, Mala Mani, Hiroshi Yasui, Yu-Tzu Tai |
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| Rok vydání: | 2007 |
| Předmět: |
Beta-catenin
Transcription Genetic Transplantation Heterologous Apoptosis Mice SCID Biology TCF/LEF family Mice Cell Line Tumor medicine Animals Humans Perylene beta Catenin Regulation of gene expression Multidisciplinary Interleukin-6 Gene Expression Profiling Wnt signaling pathway Biological Sciences Molecular biology Gene Expression Regulation Neoplastic Survival Rate Wnt Proteins medicine.anatomical_structure Cell culture Catenin biology.protein Cancer research Bone marrow Signal transduction Multiple Myeloma TCF Transcription Factors Protein Binding Signal Transduction |
| Zdroj: | Proceedings of the National Academy of Sciences. 104:7516-7521 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.0610299104 |
| Popis: | Multiple myeloma (MM) is an invariably fatal form of cancer characterized by clonal proliferation of malignant plasma cells in the bone marrow. The canonical Wnt signaling pathway is activated in MM cells through constitutively active β-catenin, a messenger molecule relevant to growth, survival, and migration of MM cells. The identification of a number of small molecular compounds, such as PKF115–584, which disrupt the interaction of the transcriptionally active β-catenin/TCF protein complex, provides valuable new therapeutic tools to target an alternative pathway in MM independent of the proteasome. Here we evaluated the transcriptional, proteomic, signaling changes, and biological sequelae associated with the inhibition of Wnt signaling in MM by PKF115–584. The compound blocks expression of Wnt target genes and induces cytotoxicity in both patient MM cells and MM cell lines without a significant effect in normal plasma cells. In xenograft models of human MM, PKF115–584 inhibits tumor growth and prolongs survival. Taken together, these data demonstrate the efficacy of disrupting the β-catenin/TCF transcriptional complex to exploit tumor dependence on Wnt signaling as a therapeutic approach in the treatment of MM. |
| Databáze: | OpenAIRE |
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