Alpha-catulin contributes to drug-resistance of melanoma by activating NF-κB and AP-1

• Published in: PloS one Vol. 10; no. 3; p. e0119402
• Main Authors: Kreiseder, Birgit, Holper-Schichl, Yvonne M, Muellauer, Barbara, Jacobi, Nico, Pretsch, Alexander, Schmid, Johannes A, de Martin, Rainer, Hundsberger, Harald, Eger, Andreas, Wiesner, Christoph
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 20.03.2015; Public Library of Science (PLoS)
• Subjects: alpha Catenin - genetics; alpha Catenin - metabolism; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - genetics; c-Jun protein; Cell adhesion & migration; Cell Line, Tumor; Cell Proliferation; Chemoresistance; Cisplatin; Cisplatin - pharmacology; Cytoskeleton; Down-regulation; Drug resistance; Drug Resistance, Neoplasm - genetics; Drugs; E-cadherin; Ectopic expression; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases - metabolism; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; JNK Mitogen-Activated Protein Kinases - metabolism; Kinases; MAP kinase; Matrix metalloproteinases; Melanoma; Melanoma - genetics; Melanoma - metabolism; Mesenchyme; Metastases; N-Cadherin; NF-kappa B - metabolism; NF-κB protein; Pharmaceuticals; Phosphorylation; Proto-Oncogene Proteins c-jun - metabolism; Skin cancer; Skin diseases; Transcription Factor AP-1 - metabolism; Transcription factors; United States > US; Austria; Texas
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0119402

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.