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

BMC Cancer

Miroslava Matuskova¹  Silvia Tyciakova¹  Barbora Svitkova¹  Valeria Valova² 

[1] Cancer Research Institute, Biomedical Research Center of Slovak Academy of Sciences, Dubravska cesta 9, 845 05, Bratislava, Slovakia;Cancer Research Institute, Biomedical Research Center of Slovak Academy of Sciences, Dubravska cesta 9, 845 05, Bratislava, Slovakia;Department of Genetics, Faculty of Natural Sciences, Comenius University, Mlynská dolina, Ilkovicova 6, 842 15, Bratislava, Slovakia;

关键词: TNFα;    Melanoma;    Senescence;    Autophagy;    Aldehyde dehydrogenase activity;    Mitochondrial status;    Cancer stem cell-related markers;   

DOI  :  10.1186/s12885-021-08237-1

来源: Springer

【 摘 要 】

BackgroundTumor necrosis factor alpha (TNFα) 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 TNFα is dependent on the type of malignant cells, with the potential to arrest cancer progression.MethodsIn order to explain the diverse cellular response to TNFα, we engineered melanoma and colorectal carcinoma cell lines stably overexpressing this cytokine.ResultsUnder the TNFα 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 TNFα/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 TNFα 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 TNFα 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.

【 授权许可】

CC BY