Gerd Birkenmeier
University of Leipzig, Institute of Biochemistry, Germany

Abstract:

The wnt/ß-catenin signal transduction pathway plays an important role in tumorigenesis. The key element is beta-catenin that interacts with the TCF/LEF transcription factors and activates wnt target genes such as myc, VEGF, MMP, cadherins, uPAR and others. Wnt protein bind to the extra-cellular domain of the Frizzled receptors, and signal transduction is mediated by assistance of low-density lipoprotein receptor-related proteins (LRPs) family members. Ligands of LRPs may interfere with the wnt/ß-catenin signal transduction and thereby inhibit tumor growth. Therefore, modulation of extra-cellular ligand level may be an option to combat cancer growth.

One of the promissing target ligands is the protease inhibitor alpha2-macroglobulin (A2M) that normally present in human plasma. This protein ligands LRP1 and impacts its expression resulting in wnt/ß-catenin inhibition [1]. Furthermore, it sequesters soluble extra-cellular Frizzle binding proteins. This multifunctional inhibitor is suggested to regulate tumor growth at various levels constituting thereby an attractive therapeutic target.

[1] Lindner et al.: Alpha2-macroglobulin inhibits the malignant properties of astrocytoma cells by impeding beta-catenin signaling. Cancer Res. (2010) 70: 277 - 87.

Keywords: Wnt/ß-catenin, Alpha2-macroglobulin; LRP1; Brain tumour, Prostate cancer