Cell adhesion inhibiting peptides exhibit potent anticancer activity and modulate intestinal microbiota

Membrane E-cadherin is one of the proteins whose expression affects cancer cell migration and adhesion. The design of peptide drugs that target such cancer cell-specific characteristics have received great attention in recent years and cysteine derivatives in particular have been shown to enhance anticancer effects. Herein, we set out to investigate the anticancer activity of a cell adhesion inhibiting peptide comprised of L-lysine (Lys) and Benzyl-L-cysteine (BnCys) and its influence on intestinal microbiota. The peptide inhibits cell migration and adhesion by interfering E-cadherin packaging, perturbing the integrity of cell membrane, and triggering caspase-3 and PARP related apoptotic pathways. It is highly possible that the cationic Lys segment would bind with the negatively charged cadherin molecules and the bulky BnCys segment would act as a spacing moiety to prevent the packing of E-cadherin. The peptide mixed with low-dose cisplatin effectively inhibits tumor growth and metastasis without incurring weight loss, prolonging the survival of tumor-bearing mice. The peptide treatment group increases the relative proportion of intestinal Akkermansia muciniphila (Akk), suggesting at prebiotic properties. These results paint a promising picture for designing cell migration/adhesion inhibiting peptides to target membrane E-cadherin for anticancer therapy.