Non-canonical activation of PAR1 induces autophagy in mammalian breast cancer cells

Abstract

Whether autophagy is a boon or a bane for the body does not have a straightforward answer, as its consequences are intricately tied to the pathophysiological context that triggers its activation. The intricate nature of the effects of autophagy on the body, compounded by its multifaceted regulation through various upstream signaling pathways, warrants a relatively highly deep and nuanced research. This study delves into 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 activation downregulates mTOR and triggers autophagy in mammalian breast cancer cells. This noncanonical activation generates an N-terminal sequence in PAR1, which, when mimicked by a synthetic peptide, induces autophagy independently of HAP. Further investigation in BALB/c mouse model of low-grade breast cancer reveals that the synthetic peptide-induced autophagy significantly inhibits tumor growth and delays carcinogenesis progression. Importantly, the lack of PAR1 expression in normal, healthy cells facilitates the peptide to selectively target cancerous cells with relatively high PAR1 expression, highlighting its potential as a therapeutic tool against low-grade breast cancer. These findings provide valuable insights into autophagy modulation via PAR1 and suggest a promising avenue for targeted cancer therapy.