Insulin-like growth factor receptor-1 as an anti-cancer target: blocking transformation and inducing apoptosis.
IGF-IR (Insulin-like growth factor receptor 1) is a tetrameric glycoprotein composed of two alpha and two beta subunits. The alpha subunit localizes extra-cellularly for ligand binding, whereas the beta 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.
Cancer Molecular Sciences, Pfizer Global Research and Development, Ann Arbor Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105, USA.
Yuli
Y
Wang
Yi
Y
Sun
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D017526:Receptor, IGF Type 1