title: Alpha-catulin contributes to drug-resistance of melanoma by activating NF-κB and AP-1.
abstract: 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.
authors: SeaLife Pharma GmbH, Tulln, Austria.
authors: Birgit
authors: B
authors: Kreiseder
authors: Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
authors: Yvonne M
authors: YM
authors: Holper-Schichl
authors: SeaLife Pharma GmbH, Tulln, Austria.
authors: Barbara
authors: B
authors: Muellauer
authors: Medical and Pharmaceutical Biotechnology, University of Applied Sciences, Krems, Austria.
authors: Nico
authors: N
authors: Jacobi
authors: SeaLife Pharma GmbH, Tulln, Austria.
authors: Alexander
authors: A
authors: Pretsch
authors: Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
authors: Johannes A
authors: JA
authors: Schmid
authors: Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
authors: Rainer
authors: R
authors: de Martin
authors: Medical and Pharmaceutical Biotechnology, University of Applied Sciences, Krems, Austria.
authors: Harald
authors: H
authors: Hundsberger
authors: Medical and Pharmaceutical Biotechnology, University of Applied Sciences, Krems, Austria.
authors: Andreas
authors: A
authors: Eger
authors: SeaLife Pharma GmbH, Tulln, Austria; Medical and Pharmaceutical Biotechnology, University of Applied Sciences, Krems, Austria.
authors: Christoph
authors: C
authors: Wiesner
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D051178:alpha Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D051178:alpha Catenin; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D002945:Cisplatin