Differential involvement of TAK1, RIPK1 and NF-κB signaling in Smac mimetic-induced cell death in breast cancer cells.

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.

• Authors: Nadine Schmidt, Lisa Kowald, Sjoerd J L van Wijk, Simone Fulda
• Journal: Biological chemistry (Biol Chem) Vol. 400 Issue 2 Pg. 171-180 (01 28 2019) ISSN: 1437-4315 [Electronic] Germany
• PMID: 30391931 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• DIABLO protein, human
• Intracellular Signaling Peptides and Proteins
• Mitochondrial Proteins
• NF-kappa B
• RNA, Messenger
• Tumor Necrosis Factor-alpha
• RIPK1 protein, human
• Receptor-Interacting Protein Serine-Threonine Kinases
• MAP Kinase Kinase Kinases
• MAP kinase kinase kinase 7

Topics

• Apoptosis Regulatory Proteins
• Biomimetics
• Breast Neoplasms (metabolism, pathology)
• Cell Death
• Cell Line, Tumor
• Humans
• Intracellular Signaling Peptides and Proteins (metabolism)
• MAP Kinase Kinase Kinases (metabolism)
• Mitochondrial Proteins (metabolism)
• NF-kappa B (metabolism)
• RNA, Messenger (genetics)
• Receptor-Interacting Protein Serine-Threonine Kinases (metabolism)
• Signal Transduction
• Tumor Necrosis Factor-alpha (genetics)
• Up-Regulation