Open AccessAlpha-Catulin Contributes to Drug-Resistance of Melanoma by Activating NF-κB and AP-1
Author(s) -
Birgit Kreiseder,
Yvonne M Holper-Schichl,
Barbara Muellauer,
Nico Jacobi,
Alexander Pretsch,
Johannes A. Schmid,
Rainer de Martin,
Harald Hundsberger,
Andreas Eger,
Christoph Wiesner
Publication year - 2015
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0119402
Subject(s) - melanoma , downregulation and upregulation , cancer research , gene knockdown , metastasis , mapk/erk pathway , apoptosis , epithelial–mesenchymal transition , cisplatin , cancer , medicine , biology , phosphorylation , microbiology and biotechnology , chemotherapy , biochemistry , gene
Melanoma is the most dangerous type of skin cancer accounting for 48,000 deaths worldwide each year and an average survival rate of about 6-10 months with conventional treatment. Tumor metastasis and chemoresistance of melanoma cells are reported as the main reasons for the insufficiency of currently available treatments for late stage melanoma. The cytoskeletal linker protein α-catulin (CTNNAL1) has been shown to be important in inflammation, apoptosis and cytoskeletal reorganization. Recently, we found an elevated expression of α-catulin in melanoma cells. Ectopic expression of α-catulin promoted melanoma progression and occurred concomitantly with the downregulation of E-cadherin and the upregulation of mesenchymal genes such as N-cadherin, Snail/Slug and the matrix metalloproteinases 2 and 9. In the current study we showed that α-catulin knockdown reduced NF-κB and AP-1 activity in malignant melanoma cells. Further, downregulation of α-catulin diminished ERK phosphorylation in malignant melanoma cells and sensitized them to treatment with chemotherapeutic drugs. In particular, cisplatin treatment led to decreased ERK-, JNK- and c-Jun phosphorylation in α-catulin knockdown melanoma cells, which was accompanied by enhanced apoptosis compared to control cells. Altogether, these results suggest that targeted inhibition of α-catulin may be used as a viable therapeutic strategy to chemosensitize melanoma cells to cisplatin by down-regulation of NF-κB and MAPK pathways.