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

Abstract

Background Tumor 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. 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.

Effects of Dityrosine on Lactic Acid Metabolism in Mice Gastrocnemius Muscle During Endurance Exercise via the Oxidative Stress-Induced Mitochondria Damage

“…84 Second, TLR4 activation in cells can impact the expression of various inflammatory cytokines, including TNFα and IL-6, 85 ultimately leading to alterations in mitochondrial status, decreased ATP production, and changes in mitochondrial morphology. 86,87 We observed an increase in TLR4, NFκB, TNFα, and IL-6 levels in both blood and the gastrocnemius muscle due to Dityr treatment. Dityr exposure also significantly increased the protein level of NFκB in both the cytoplasm and nucleus.…”

The involvement of RIPK4 in TNF-α-stimulated IL-6 and IL-8 production by melanoma cells

“…We postulate that the attenuated signal transduction triggered by TNF-α is a consequence of the reduced expression of the TRAF1 and TNFRSF9 receptors. Tyciakova observed that TNF-α overexpression is accompanied by a significant upregulation of the proinflammatory cytokine IL-6 gene in A375 melanoma cells and proapoptotic ligand TRAIL gene in colorectal cancer cell HT29, both of which were mediated by TNF-α/TNFR1 signaling (Tyciakova et al 2021 ). On the contrary, our study suggests that RIPK4 may regulate IL-8 expression by involving in the MAPK kinase cascade and NF-κB.…”

Secretory Factors from Calcium-Sensing Receptor-Activated SW872 Pre-Adipocytes Induce Cellular Senescence and A Mitochondrial Fragmentation-Mediated Inflammatory Response in HepG2 Cells

“…In senescent cells, mitochondrial alterations such as fragmentation in the mitochondrial network or loss in the Δψ are common features [ 52 , 53 ]. Our results coincide with those reported in colon and melanocyte cell lines exposed to overexpression of TNF-α, which decreased the Δψ and increased the fragmentation of the mitochondrial network.…”

“…Our results coincide with those reported in colon and melanocyte cell lines exposed to overexpression of TNF-α, which decreased the Δψ and increased the fragmentation of the mitochondrial network. After an early process of apoptosis, the remaining cells show mitochondrial dysfunction and increased cytokine expression, which is associated with cellular senescence [ 53 ]. The evidence on altered mitochondrial dynamics and cellular senescence is under discussion because the results may vary depending on the cell type under study [ 22 , 54 ].…”