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.

Phenotype-based variation as a biomarker of sensitivity to molecularly targeted therapy in melanoma

“…The “stemness” of melanoma cells is thought to exist in a dynamic state, as melanoma cells with stem-cell markers have been reported to arise from cells lacking these markers, stem-cell like melanoma cells might not be required for tumor initiation, and the stem- and non-stem-cell phenotypes can switch dynamically 7, 14 . Similar to the plasticity reported for stemness in melanoma, epithelial-to-mesenchymal transition (EMT) has also been implied as a factor driving metastasis and causing drug resistance in melanoma 15, 16 . Thirdly, melanoma specific in vitro analyses aiming primarily to explain differing metastatic potential generated gene lists that could robustly classify melanoma cell lines or tumor cells into either a “proliferative” or an “invasive” character 6, 17, 18 ; and switching among these phenotypes was also shown as well 5, 14 .…”

The Tumor-Promoting Role of TRIP4 in Melanoma Progression and its Involvement in Response to BRAF-Targeted Therapy

“…However, therapy cessation gradually develops because of acquired resistance to these agents. Several mechanisms responsible for the acquired resistance have been described, including reactivation of the NF-kB pathway (Heinecke et al, 2014;Kreiseder et al, 2015;Manzano et al, 2016). Given the regulation of COX-2/iNOS expression mediated by TRIP4 and its activation on NF-kB signaling, our studies provide a candidate hypothesis and evidence for the functional role of TRIP4 expression in modulating acquired resistance to BRAFtargeted therapies.…”

SANTAMARINE: Mechanistic studies on multiple diseases

“…The abnormal activation of NF‐κB signaling pathway plays an important role in tumor (Karin, ). NF‐кB regulates the expression of different anti‐apoptotic genes, which encourages drug resistance in pancreatic cancer, melanoma, gastric cancer, lung cancer, and hepatocellular carcinoma (Jeon et al, ; Jung et al, ; Kreiseder et al, ; Zhang et al, ). SLs inhibit the activation of NF‐kB in various cancer cells.…”