A peptide-induced regression of low-grade malignant breast tumor via activation of autophagy in breast cancer cells

Peptides have recently gained much attention for their therapeutic role in several diseases without having significant side effects. These are short chain amino acids and can be synthesized chemically with a great extent of purity, which renders them very effective, precise and safe for the body. So far, very few artificially synthesized peptides have been developed that have autophagy-inducing properties. Among them, a very small number of peptides have been demonstrated to have anti-tumorigenic effect by modulating autophagy with most of them lacking specificity for target cells. This study aims to investigate the regulation of autophagy through noncanonical activation of protease-activated receptor 1 (PAR1) by hemagglutinin protease (HAP). Unlike the canonical activation of PAR1 by thrombin, which enhances cell proliferation via mechanistic target of rapamycin (mTOR) signaling, HAP-induced noncanonical activation downregulates mTOR activation and triggers autophagy in both estrogen receptor positive/ progesterone receptor positive/ HER2 negative (ER+/PR+/HER2-) and triple negative (ER-/PR-/HER2-) breast cancer cells. This noncanonical activation generates a N-terminal sequence in PAR1. When this sequence is mimicked by a synthetic peptide, it induces autophagy independently of HAP in the breast cancer cells in vitro. Further in vivo investigation in BALB/c mouse model of low-grade malignant breast tumor reveals that the peptide-induced autophagy significantly inhibits tumor growth and delays tumor progression. Importantly, the lack of PAR1 expression in normal, healthy breast epithelial cells facilitates the peptide to selectively target breast cancer cells with relatively high PAR1 expression, highlighting its potential as a therapeutic agent against low-grade malignant breast tumor. These findings provide valuable insights into autophagy activation by a synthetic peptide that targets breast cancer cells with high PAR1 expression and for the first time shows peptide mediated targeted therapy of low-grade malignant breast tumor.