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Fig. 6 | Breast Cancer Research

Fig. 6

From: Combined the SMAC mimetic and BCL2 inhibitor sensitizes neoadjuvant chemotherapy by targeting necrosome complexes in tyrosine aminoacyl-tRNA synthase-positive breast cancer

Fig. 6

The proposed mechanism underlying the synergistic effects of LCL161 (SMAC mimetic) and ABT-263 (Navitoclax, pan-BCL2 inhibitor) through YARS-induced necroptosis in breast cancer. Upon overexpression of YARS, the accumulation of ROS in the mitochondria, inducing mitochondrial outer membrane permeabilization (MOMP), is triggered; this is followed by the release of SMAC into the cytosol and reduced ATP generation. LCL161 (SMAC mimetic), a cIAPs antagonist, induces cell death through caspase activation. The LCL161-mediated depletion of cIAPs proteins leads to necroptosis. During necroptosis, RIPK interacts with RIPK3 and MLKL to form the necrosome complex, which promotes the activation of RIPK3 and MLKL; subsequently, MLKL oligomerizes and translocates to and forms pores in the plasma membrane, leading to plasma membrane disruption. ABT-263 directly binds to and neutralizes pro-survival BCL2-like proteins, aiding the induction of necroptosis. The synergistic effect of LCL161 and ABT-263 leads to the phosphorylation of the necrosome complex, and inhibition of pan-caspase might have implications as a new therapeutic modality for treatment in breast cancer

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