Overexpression of TNF[alpha] induces senescence, autophagy and mitochondrial dysfunctions in melanoma cells

Background Tumor 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 poten...

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Bibliographic Details
Published in:BMC cancer 2021-05, Vol.21 (1)
Main Authors: Tyciakova, Silvia, Valova, Valeria, Svitkova, Barbora, Matuskova, Miroslava
Format: Article
Language:English
Subjects:
Apoptosis
Autophagy (Cytology)
Cancer cells
Colorectal cancer
Development and progression
Gene expression
Genetic aspects
Health aspects
Melanoma
Mitochondria
Stem cells
Tumor necrosis factor
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Summary:Background Tumor 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. Methods In order to explain the diverse cellular response to TNF[alpha], we engineered melanoma and colorectal carcinoma cell lines stably overexpressing this cytokine. Results Under 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. Conclusions Our 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. Keywords: TNF[alpha], Melanoma, Senescence, Autophagy, Aldehyde dehydrogenase activity, Mitochondrial status, Cancer stem cell-related markers
ISSN:1471-2407
1471-2407
DOI:10.1186/s12885-021-08237-1