Overexpression of TNFα induces senescence, autophagy and mitochondrial dysfunctions in melanoma cells

BackgroundTumor necrosis factor alpha (TNF alpha) is a pleiotropic cytokine with both anti-tumorigenic and pro-tumorigenic activity, affecting tumor cell biology, the balance between cell survival and death. The final effect of TNF alpha is dependent on the type of malignant cells, with the potential to arrest cancer progression.MethodsIn order to explain the diverse cellular response to TNF alpha, we engineered melanoma and colorectal carcinoma cell lines stably overexpressing this cytokine.ResultsUnder the TNF alpha overexpression, significant upregulation of two genes was observed: proinflammatory cytokine IL6 gene in melanoma cells A375 and gene for pro-apoptotic ligand TRAIL in colorectal carcinoma cells HT29, both mediated by TNF alpha /TNFR1 signaling. Malignant melanoma line A375 displayed also increased autophagy on day 3, followed by premature senescence on day 6. Both processes seem to be interconnected, following earlier apoptosis induction and deregulation of mitochondrial functions. We documented altered mitochondrial status, lowered ATP production, lowered mitochondrial mass, and changes in mitochondrial morphology (shortened and condensed mitochondria) both in melanoma and colorectal carcinoma cells. Overexpression of TNF alpha was not linked with significant affection of the subpopulation of cancer stem-like cells in vitro. However, we could demonstrate a decrease in aldehyde dehydrogenase (ALDH) activity up to 50%, which is associated with to the stemness phenotype.ConclusionsOur in vitro study of direct TNF alpha influence demonstrates two distinct outcomes in tumor cells of different origin, in non-epithelial malignant melanoma cells of neural crest origin, and in colorectal carcinoma cells derived from the epithelium.

Automated summary

The study reveals that TNF alpha has different effects on malignant tumor cells of different origins, potentially influencing cellular biological processes such as autophagy, apoptosis, and mitochondrial function through regulation of proinflammatory cytokines and pro-apoptotic ligand genes.