Targeting leucine-rich alpha-2-glycoprotein-1 (LRG1) and the LRG1-cytochrome c-Apaf-1 axis in cancer therapy (IMAGE)
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Figure 3. Schematic cartoon of the LRG1-Cyt c-Apaf-1 axis in a cell treated with both the anti-LRG1 mAb and a nano-PROTAC to degrade LRG1 in the cytoplasm. The anti-LRG1 mAb, magacizumab blocks signaling through EGFR family members and the cancer cell remains poised to respond to apoptotic insults. Decreased expression of Bcl-2 allows Bax to oligomerize in the mitochondrial outer membrane and facilitate the translocation of Cyt c to the cytoplasm. Delivery of the nano-PROTAC into the cytoplasm leads to its association with both LRG1 and the ligand for E3 ubiquitin ligase, which recruits the enzyme for attaching ubiquitin to LRG1. The glycoprotein is then degraded in the proteasome. In the absence of competition from cytoplasmic LRG1, Apaf-1 binds Cyt c that is released from mitochondria into the cytoplasm and initiates caspase activation, culminating in apoptosis.
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Copyright: © 2026 Jemmerson. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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