Differential involvement of TAK1, RIPK1 and NF-κB signaling in Smac mimetic-induced cell death in breast cancer cells.
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.
['Schmidt|Nadine|N|', 'Kowald|Lisa|L|', 'van Wijk|Sjoerd J L|SJL|', 'Fulda|Simone|S|']
D051017:Apoptosis Regulatory Proteins D032701:Biomimetics D001943:Breast Neoplasms D016923:Cell Death D045744:Cell Line, Tumor D006801:Humans D047908:Intracellular Signaling Peptides and Proteins D020930:MAP Kinase Kinase Kinases D024101:Mitochondrial Proteins D016328:NF-kappa B D012333:RNA, Messenger D053422:Receptor-Interacting Protein Serine-Threonine Kinases D015398:Signal Transduction D014409:Tumor Necrosis Factor-alpha D015854:Up-Regulation
NF-κB cell death breast cancer Smac mimetics gene expression