Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction

摘要: Isthmin (ISM) is a secreted 60-kDa protein that potently induces endothelial cell (EC) apoptosis. It suppresses tumor growth and angiogenesis in mice when stably overexpressed cancer cells. Although αvβ5 integrin serves as low-affinity receptor for ISM, the mechanism by which ISM mediates antiangiogenesis apoptosis ECs remain to be fully resolved. In this work, we report identification of cell-surface glucose-regulated 78 kDa (GRP78) high-affinity (Kd=8.6 nM). We demonstrated ISM-GRP78 interaction triggers not only activated but also cells expressing high level GRP78. Normal benign tend express low GRP78 are resistant ISM-induced Upon binding GRP78, internalized into through clathrin-dependent endocytosis essential its proapoptotic activity. Once inside cell, co-targets with mitochondria where it interacts ADP/ATP carriers on inner membrane blocks ATP transport from cytosol, thereby causing Hence, novel ligand targets trigger inducing mitochondrial dysfunction. The restricted high-level expression make them uniquely susceptible ISM-targeted Indeed, systemic delivery recombinant suppressed subcutaneous 4T1 breast carcinoma B16 melanoma eliciting selectively ECs. Together, work reveals pathway demonstrates potential cancer-specific dual-targeting anticancer agent.