Abstract
Smac mimetics (SMs) are considered promising cancer therapeutics. However, the mechanisms responsible for mediating cell death by SMs are still only partly understood. Therefore, in this study, we investigated signaling pathways upon treatment with the bivalent SM BV6 using two SM-sensitive breast cancer cell lines as models. Interestingly, genetic silencing of transforming growth factor (TGF)β activated kinase (TAK)1, an upstream activator of the nuclear factor-kappaB (NF-κB) subunit RelA (p65), increased BV6-induced cell death only in EVSA-T cells, although it reduced BV6-mediated upregulation of tumor necrosis factor (TNF)α in both EVSA-T and MDA-MB-231 cells. By comparison, genetic silencing of p65, a key component of canonical NF-κB signaling, blocked BV6-induced cell death in MDA-MB-231 but not in EVSA-T cells. Similarly, knockdown of NF-κB-inducing kinase (NIK) rescued MDA-MB-231 cells from BV6-induced cell death, while it failed to do so in EVSA-T cells. Consistently, silencing of p65 or NIK reduced BV6-stimulated upregulation of TNFα in MDA-MB-231 cells. In conclusion, TAK1, receptor-interacting kinase 1 (RIPK1) as well as canonical and non-canonical NF-κB signaling are differentially involved in SM-induced cell death in breast cancer cells. These findings contribute to a better understanding of SM-induced signaling pathways.
Acknowledgments
The expert secretarial assistance of C. Hugenberg is greatly appreciated. Funding: this work has been partly supported by grants from the DFG and BMBF (to S. F.).
Conflict of interest statement: None to declare.
References
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Supplementary Material
The online version of this article offers supplementary material (https://doi.org/10.1515/hsz-2018-0324).
©2019 Walter de Gruyter GmbH, Berlin/Boston
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Articles in the same Issue
- Frontmatter
- Mitochondria, Apoptosis and Cancer (MAC) 2017
- Transglutaminase type 2 in the regulation of proteostasis
- Mitochondria-driven elimination of cancer and senescent cells
- Comparative study of the differential cell death protecting effect of various ROS scavengers
- Involvement of mitophagy in cisplatin-induced cell death regulation
- Differential involvement of TAK1, RIPK1 and NF-κB signaling in Smac mimetic-induced cell death in breast cancer cells
- Selective BH3-mimetics targeting BCL-2, BCL-XL or MCL-1 induce severe mitochondrial perturbations
- BNIP3 contributes to the glutamine-driven aggressive behavior of melanoma cells
- Review
- Multiple binding sites in organic cation transporters require sophisticated procedures to identify interactions of novel drugs
- Research Articles/Short Communications
- Membranes, Lipids, Glycobiology
- Characterization of the cholesterol efflux of apolipoprotein E-containing high-density lipoprotein in THP-1 cells
- Advanced glycation endproducts and polysialylation affect the turnover of the neural cell adhesion molecule (NCAM) and the receptor for advanced glycation endproducts (RAGE)
- Cell Biology and Signaling
- miR-34a-5p aggravates hypoxia-induced apoptosis by targeting ZEB1 in cardiomyocytes
- MicroRNA-1225-5p acts as a tumor-suppressor in laryngeal cancer via targeting CDC14B
- Novel Techniques
- Tandem DNAzyme for double digestion: a new tool for circRNA suppression