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.
Highlights
Malignant melanoma is an aggressive and chemoresistant type of skin cancer that originates in melanocytes [1, 2]
We found that α-catulin increased already the basal NF-ĸB activity in melanocytes in a concentration dependent manner, but further augmented NF-ĸB activation in a highly significant manner when cotransfected with IKKβ or stimulated with TNFα or LPS for 8 h (Fig. 1A)
Down-regulation of α-catulin significantly decreased the level of the NF-ĸB-luciferase reporter in all three melanoma cell lines (Fig. 1D; n.s. versus sh-catu1 and sh-catu2). α-Catulin knockdown decreased NF-ĸB activity after TNFα, LPS, HGF- and Serum (10% FCS) activation in Melanoma 7 cells (Fig. 1E), which is consistent with our previous finding that α-catulin is central for mediating NF-ĸB activation
Summary
Malignant melanoma is an aggressive and chemoresistant type of skin cancer that originates in melanocytes [1, 2]. Less than 5% of skin cancers are melanoma, it causes a large majority of skin cancer related deaths [3]. The poor prognosis for late stage melanoma patients is due to the low response rates to conventional chemotherapy treatments with dacarbazine or its derivative temozolomide, that are below 20% [4, 5]. The platinum analog cisplatin is known to PLOS ONE | DOI:10.1371/journal.pone.0119402. Alpha-Catulin, a Potential Target for Melanoma Therapy The platinum analog cisplatin is known to PLOS ONE | DOI:10.1371/journal.pone.0119402 March 20, 2015
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