Abstract
Beta-catenin plays an important role in embryogenesis and carcinogenesis by controlling either cadherin-mediated cell adhesion or transcriptional activation of target gene expression. In many types of cancers nuclear translocation of beta-catenin has been observed. Our data indicate that during melanoma progression an increased dependency on the transcriptional function of beta-catenin takes place. Blockade of beta-catenin in metastatic melanoma cell lines efficiently induces apoptosis, inhibits proliferation, migration and invasion in monolayer and 3-dimensional skin reconstructs and decreases chemoresistance. In addition, subcutaneous melanoma growth in SCID mice was almost completely inhibited by an inducible beta-catenin knockdown. In contrast, the survival of benign melanocytes and primary melanoma cell lines was less affected by beta-catenin depletion. However, enhanced expression of beta-catenin in primary melanoma cell lines increased invasive capacity in vitro and tumor growth in the SCID mouse model. These data suggest that beta-catenin is an essential survival factor for metastatic melanoma cells, whereas it is dispensable for the survival of benign melanocytes and primary, non-invasive melanoma cells. Furthermore, beta-catenin increases tumorigenicity of primary melanoma cell lines. The differential requirements for beta-catenin signaling in aggressive melanoma versus benign melanocytic cells make beta-catenin a possible new target in melanoma therapy.
Highlights
The canonical Wnt/b-catenin signaling pathway plays a key role in embryogenesis and cellular homeostasis and regulates cell fate, differentiation, proliferation and self-renewal of stem cells and progenitor cells
In this study we show that b-catenin is an essential survival factor for aggressive metastatic melanoma cell lines, but is dispensable for proliferation of normal human melanocytes and primary melanoma cell lines
We show that bcatenin is a key factor determining invasive capacity and tumorigenicity of primary and metastatic melanoma cell lines
Summary
The canonical Wnt/b-catenin signaling pathway plays a key role in embryogenesis and cellular homeostasis and regulates cell fate, differentiation, proliferation and self-renewal of stem cells and progenitor cells. B-catenin-TCF/LEF signaling activity was higher in metastatic compared to non-metatastatic melanoma cell lines as determined by a Super8xTOPflash reporter assay (Figure 1A) These data suggest that the transcriptional activity of b-catenin increases during melanoma progression. The tumorigenic potential of nonmetastatic (WM115, WM793) and metastatic (SKMel28, 451LU, Mewo) melanoma cell lines in a soft agar growth assay was efficiently inhibited in a PKF115–584 dose-dependent manner (Figure 2C) We confirmed this by inducible expression of shRNA against b-catenin in SKMel and 451LU cells (Figure 2C). These data show that b-catenin downregulation in primary and metastatic melanoma cell lines inhibit migration and invasion in monolayer culture as well as in physiological skin equivalents. These data indicate that bcatenin is critically involved in chemoresistance of melanoma cells
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