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Current Cancer Drug Targets
ISSN (Print): 1568-0096
ISSN (Online): 1873-5576
VOLUME: 2
ISSUE: 3
DOI: 10.2174/1568009023333863      Price:  $58









Insulin-Like Growth Factor Receptor-1 as an Anti-Cancer Target: Blocking Transformation and Inducing Apoptosis

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Author(s): Yuli Wang and Yi Sun
Pages 191-207 (17)
Abstract:
IGF-IR (Insulin-like growth factor receptor 1) is a tetrameric glycoprotein composed of two α and two β subunits. The α subunit localizes extra-cellularly for ligand binding, whereas the β subunit consists of transmembrane chains and a cytoplasmic tyrosine kinase domain for enzymatic activity. IGF-IR ligands, IGF-I and IGF-II, are mitogens and survival factors for many cancer cells. Binding of ligands to the IGF-IR initiates a cascade of events leading to activation of signal transduction pathways, mainly MAPK and PI-3K pathways, to stimulate proliferation / mitogenesis, to induce neoplastic transformation, to inhibit apoptosis, and to promote angiogenesis and metastasis. It has been shown that the presence of IGF-IR was required for transformation induced by many oncogenes and over-expression or constitutive activation of IGF-IR gave rise to transformed phenotypes. Significantly, over-expression of IGF-IR was observed in multiple human cancers including carcinomas of breast, lung, colon, and prostate. Patients with IGF-IR positive cancers had a worse prognosis in some cases. Furthermore, down-regulation or functional inactivation of IGF-IR sensitized tumor cells to apoptosis and reversed tumor cell phenotype. Thus, IGF-IR appears to be a promising cancer target. Indeed, a variety of approaches aimed at targeting IGF-IR have been utilized to prove the concept, or are being developed for potential anticancer therapies. These include targeting functional IGF-IR on cell surface, targeting ligand / receptor interaction, targeting receptor expression and functions, and targeting receptor kinase activity. Cancer patients could eventually benefit from the development of these specific IGF-IR antagonists.
Keywords:
anti-cancer target, inducing apoptosis, angiogenesis and metastasis, biological outcomes, igf-ir expression, transformation, cysteine protease inhibitor, autophosphorylation
Affiliation:
Cancer Molecular Sciences,Pfizer Global Research and Development, Ann Arbor Laboratories, 2800Plymouth Road, Ann Arbor, MI 48105, USA