Non-canonical activation of PAR1 induces autophagy in mammalian breast cancer cells
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The question of whether autophagy is a boon or a bane for the body does not lend itself to a straightforward answer, as its consequences are intricately tied to the pathophysiological context that triggers its activation. The intricate nature of autophagy’s effects on the body, compounded by its multifaceted regulation through various upstream signaling pathways, warrants a deeper and more nuanced research. This study delves into the regulation of autophagy through the non-canonical activation of protease activated receptor 1 (hereafter, termed as PAR1) by Hemagglutinin protease (hereafter, referred as HAP). In contrast to the canonical activation of PAR1 by thrombin, which promotes cell proliferation via the upregulation of mTOR signaling, HAP-induced, non-canonical activation of PAR1 triggers autophagy by downregulating mTOR activation and modulating subsequent key signaling pathways in mammalian breast cancer cells. This non-canonical activation results in the generation of a new N-terminal sequence of PAR1. Moreover, synthetic peptide designed to replicate this newly generated N-terminal sequence effectively triggers autophagy in mammalian breast cancer cells, thereby establishing that induction of autophagy via non-canonical PAR1 activation is independent of the activating agent of PAR1 itself. The study also explores the implications of peptide-induced autophagy in the context of early-stage, low-grade breast cancer using a BALB/c mouse model, demonstrating substantial inhibition of tumor growth and a delay in carcinogenesis progression. Importantly, the absence of notable PAR1 expression in normal, healthy cells ensures that they remain unaffected by the peptide, positioning it as a promising candidate for targeted therapy in low-grade breast cancer.