Roles of p38α and p38β mitogen-activated protein kinase isoforms in human malignant melanoma A375 cells

Skin cancer is one of the most common cancers worldwide. Melanoma accounts for similar to 5% of skin cancers but causes the large majority of skin cancer-related deaths. Recent discoveries have shown that the mitogen-activated protein kinase (MAPK) signaling pathway is critical for melanoma development and progression. Many oncogenic pathways that cause melanoma tumorigenesis have been identified, most of which are due to RAF/MEK/ERK (MAPK) pathway activation. However, the precise role of p38 remains unclear. Using specific short hairpin (sh) RNA to silence p38 alpha and p38 beta, the present findings demonstrated that p38 alpha was a crucial factor in regulating cell migration in the A375 melanoma cell line. Silencing p38 alpha downregulated the expression of epithelial-mesenchymal transition markers, such as matrix metallopeptidase (MMP) 2, MMP9, twist family bHLH transcription factor 1, snail family transcriptional repressor 1 and vimentin, while mesenchymal-epithelial transition markers, such as E-cadherin, were upregulated. Of note, the results also demonstrated that p38 alpha silencing impaired vascular endothelial growth factor expression, which regulates tumor angiogenesis. Furthermore, p38 alpha knockdown inhibited cell proliferation in melanoma cells. In addition, silencing p38 alpha induced senescence-like features, but not cell cycle arrest. Expression of the senescence markers p16, p21, p53 and beta-galactosidase was upregulated, and an increase in the number of senescence-associated beta-galactosidase-positive cells was observed in a p38 alpha knockdown stable clone. However, no significant difference was found between control and p38 beta stable knockdown cells. Taken together, the present results suggested that p38 alpha knockdown impaired migration and proliferation, and increased senescence, in A375 melanoma cells. However, p38 beta may not be involved in melanoma tumorigenesis. Therefore, targeting p38 alpha may be a valuable approach towards inhibiting tumor growth and metastasis in patients with melanoma.