Clustering\nof the Membrane Protein by Molecular Self-Assembly\nDownregulates the Signaling Pathway for Cancer Cell Inhibition

This work reports a cyclic peptide appended self-assembled\nscaffold\nthat recognizes the membrane protein EGFR and arrests the EGFR signaling\nthrough multivalent interactions by assembly-induced aggregation.\nWhen incubated with cells, the oligomers of <b>PAD-1</b> first\nrecognize the overexpressed EGFR on cancer cell membranes for arresting\nEGFR, which then initiates cellular uptake through endocytosis. The\naccumulation of <b>PAD-1</b> and EGFR in the lysosome results\nin the formation of nanofibers, leading to the lysosomal membrane\npermeabilization (LMP). These processes disrupt the homeostasis of\nEGFR and inhibit the downstream signaling transduction of EGFR for\ncancer cell survival. Moreover, LMP induced the release of protein\naggregates that could generate endoplasmic reticulum (ER) stress,\nresulting in cancer cell death selectively. In vivo studies indicate\nthe efficient antitumor efficiency of <b>PAD-1</b> in tumor-bearing\nmice. As a first example, this work provides an alternative strategy\nfor controlling protein behavior for tuning cellular events in living\ncells.