Please use this identifier to cite or link to this item: http://scholarbank.nus.edu.sg/handle/10635/48388
Title: MECHANISTIC CHARACTERIZATION OF ISTHMIN IN ANGIOGENIC INHIBITION
Authors: CHEN MO
Keywords: Isthmin, GRP78, angiogenesis, cancer, endocytosis
Issue Date: 22-Aug-2013
Source: CHEN MO (2013-08-22). MECHANISTIC CHARACTERIZATION OF ISTHMIN IN ANGIOGENIC INHIBITION. ScholarBank@NUS Repository.
Abstract: Isthmin (ISM) is a secreted 60 kDa protein potently inducing endothelial cell (EC) apoptosis and suppressing angiogenesis and tumor growth in mice when stably overexpressed in cancer cells. However, its prospect as an anti-cancer drug and mechanism in angiogenic inhibition remain to be fully resolved. In this work, it was demonstrated that systemically delivered recombinant ISM potently suppresses B16 melanoma and 4T1 breast carcinoma growth. ISM triggers apoptosis in both tumor cells and tumor ECs. In addition, glucose-regulated protein 78 (GRP78) was identified as a novel high-affinity receptor mediating ISM internalization through clathrin-dependent endocytosis and co-targeting with ISM to mitochondria. ISM-GRP78 interaction only triggers apoptosis in cells exhibiting high level of cell-surface GRP78. Inside mitochondria, ISM blocks ATP transport through interacting with ADP/ATP carriers (AACs) thus causing apoptosis. This work suggested the potential application of ISM in anti-cancer therapy and provided a novel anti-angiogenic model of ISM through GRP78-mediated endocytosis.
URI: http://scholarbank.nus.edu.sg/handle/10635/48388
Appears in Collections:Ph.D Theses (Open)

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