Fig. 1: Differential expression of TNF superfamily pathway components underlies the killing of TN-BC by Smac mimetics compared with ER-positive BC. | Cell Death & Disease

Fig. 1: Differential expression of TNF superfamily pathway components underlies the killing of TN-BC by Smac mimetics compared with ER-positive BC.

From: Taking aim with IAP antagonists at triple-negative breast cancer: a moving target no more?

Fig. 1

Schematic of death receptor signaling pathways for TNF-α, FasL, and TRAIL with ultimate cell fate outcomes shown (survival outcomes boxed in green, death outcomes boxed in red). Also indicated in three levels of red fill color (based on RNA −log10 p values) are components that are upregulated in the TCGA database for TN-BC compared with ER-positive BC. While three levels of blue fill color (based on RNA −log10 p values) are components that are downregulated in the TCGA database for TN-BC compared with ER-positive BC. Components in white fill are not indicated in the report6. The yellow drug capsule represents the small-molecule IAP antagonists known as Smac mimetics (SMs), which have multiple effects illustrated here. SMs induce the degradation of cIAP1 and cIAP2 thereby stopping TNF-α/TNFR1 triggered RIPK1 ubiquitination that blocks NF-κB and AP-1 activation and shunts RIPK1 into death complexes, referred to as the ripoptosome (RIPK1, FADD, and caspase-8) or the necrosome (RIPK1, RIPK3, and MLKL). SMs can also derepress XIAP’s ability to inhibit caspase-3, which sensitizes cells to FasL- or TRAIL-induced killing. SMs can also cause the induction of TNF-α through the activation of the alternative NF-κB pathway (not illustrated here). Activated caspase-8 is able to suppress necroptosis by cleavage of RIPK1 and RIPK3 proteins.

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