Overexpression of TNFα induces senescence, autophagy and mitochondrial dysfunctions in melanoma cells
| Main Authors: | Silvia Tyciakova, Valeria Valova, Barbora Svitkova, Miroslava Matuskova |
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| Format: | Article Journal |
| Bahasa: | eng |
| Terbitan: |
, 2021
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| Subjects: | |
| Online Access: |
https://zenodo.org/record/4783424 |
Daftar Isi:
- Background: Tumor necrosis factor alpha (TNFα) is a pleiotropic cytokine with both anti-tumorigenic and protumorigenic 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. Methods: In order to explain the diverse cellular response to TNFα, we engineered melanoma and colorectal carcinoma cell lines stably overexpressing this cytokine. Results: Under 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. Conclusions: Our 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.
- This work was supported by VEGA grants no. 02/178/17, 02/0050/19; by Ministry of Health of the Slovak Republic under the project registration number 2019/60-BMCSAV-4, EU Horizon 2020 Research and Innovation programme under grant agreement No 857381 (VISION), by UVP BIOMED – project ITMS 26240220087 and by Slovak Cancer Research Foundation RFL2009 and RFL2012 programs. The funding did not affect the design of the study, collection, analysis or interpretation of data or preparation of the manuscript.