Abstract
Malignant transformation of melanocytes frequently coincides with loss of E-cadherin expression. Here, we show that loss of E-cadherin leads to induction of nuclear factor kappa B (NFκB) activity in melanoma cell lines. Melanoma cells show constitutively active NFκB, whereas no activity is found in primary melanocytes. After re-expression of E-cadherin in melanoma cells, strong downregulation of NFκB activity was found. Consistently, NFκB activity was induced in primary human melanocytes after inhibition of E-cadherin activity by functionally blocking anti-E-cadherin antibodies. Interestingly, re-expression of E-cadherin-blocked p38 MAPK activity and the p38 MAPK inhibitors SB203580 and SB202190 almost completely prevented NFκB activation in melanoma cells. Furthermore, cytoplasmatic β-catenin induced p38 and NFκB activation in malignant melanoma. To our knowledge, this is the first report suggesting a correlation between E-cadherin and NFκB activity in melanocytes and melanoma cells. In summary, we conclude that loss of E-cadherin and cytoplasmatic β-catenin induces p38-mediated NFκB activation, potentially revealing an important mechanism of tumorigenesis in malignant melanomas.
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Abbreviations
- ELISA:
-
enzyme-linked immunosorbent assay
- EMSA:
-
electrophoretic mobility shift assay
- ERK:
-
extracellular signal-regulated protein kinase
- IκB (IkappaB):
-
inhibitor of NFκB
- IL-8:
-
interleukin 8
- JNK:
-
c-jun NH2-terminal kinase
- MAPK:
-
mitogen-activated protein kinase
- Mekk1:
-
MAP kinase kinase1
- MMP2:
-
matrix-metalloproteinase 2
- NFκB:
-
nuclear factor kappa B
- NHEM:
-
normal human epidermal melanocytes
- PBS:
-
phosphate-buffered saline
- PD98059:
-
2-(2′amino-3′-methoxyphenyl)-oxanaphthalen-4-one
- PKB:
-
protein kinase B
- RT:
-
reverse transcription
- SAPK:
-
stress-activated protein kinase
- SB202190:
-
4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole
- SB203580:
-
4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole
- TCF:
-
T-cell factor
- TGFβ2:
-
transcriptional growth factor beta 2
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Acknowledgements
We are indebted to Astrid Hamm and Claudia Abschlag for technical assistance and to Eric Fearon and Gabriele Handschuh for providing β/-γ-catenin- and pBAT-E-cadherin expression vectors, respectively. We thank Guy Haegeman for helpful discussions. This work was supported by grants from the Deutsche Forschungsgemeinschaft (DFG) to AB.
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Kuphal, S., Poser, I., Jobin, C. et al. Loss of E-cadherin leads to upregulation of NFκB activity in malignant melanoma. Oncogene 23, 8509–8519 (2004). https://doi.org/10.1038/sj.onc.1207831
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DOI: https://doi.org/10.1038/sj.onc.1207831
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