Clustering of the Membrane Protein by Molecular Self-assembly Downregulates Signaling Pathway for Cancer Cell Inhibition

This work reports a cyclic peptide appended self-assembled scaffold that recognizes the membrane protein EGFR and arrests the EGFR signaling by assembly induced aggregation through multivalent interactions. Being incubating with cells, the oligomers of PAD-1 first recognize overexpressed EGFR on cancer cell membrane for arresting EGFR, which then initiate cellular uptake through endocytosis. The accumulation of PAD-1 and EGFR in the lysosome results in the formation of nanofibers, leading to lysosomal membrane permeabilization (LMP). These processes disrupt the homeostatic of EGFR and inhibit the downstream signaling transduction of EGFR for cancer cell survive. Moreover, LMP induced the releasing of protein aggregates could generate endoplasmic reticulum (ER) stress, resulting in cancer cell death selectively. In vivo studies indicate the efficient anti-tumor efficiency of PAD-1 in tumor bearing mice. As a first example, this work provides an alternative strategy for controlling protein behavior for tuning cellular events in living cells.