Belfiore Antonino
Department of Clinical and Experimental Medicine, Endocrine Unit, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy.
Curr Pharm Des. 2007;13(7):671-86. doi: 10.2174/138161207780249173.
This review will focus on the emerging role of the insulin receptor (IR) in cancer. Several epidemiological studies have shown that insulin resistance states, characterized by hyperinsulinemia, are associated with an increased risk for a number of malignancies, including carcinomas of the breast, prostate, colon and kidney. Recent data have elucidated some molecular mechanisms by which IR is involved in cancer. First, IR is overexpressed in several human malignancies. Interestingly, one of the two IR isoform (IR-A) is especially overexpressed in cancer. IR-A is the IR fetal isoform and has the peculiar characteristic to bind not only insulin but also IGF-II. Second, IR forms hybrid receptors with the homologous IGF-IR, which is also commonly overexpressed in cancer. These hybrid receptors containing IR-A hemidimers have broad binding specificity as they bind IGF-I and also IGF-II and insulin. By binding to hybrid receptors, insulin may stimulate specific IGF-IR signaling pathways. Overexpression of IR-A is, therefore, a major mechanism of IGF system overactivation in cancer. These findings may have important implications for both the prevention and treatment of common human malignancies. They underline the concept that hyperinsulinemia, associated with insulin resistance and obesity, should be treated by changes in life style and/or pharmachological approaches to avoid an increased risk for cancer. IR-A isoform and hybrid receptors should be regarded, therefore, as potential molecular targets for novel anti-cancer therapies.
本综述将聚焦胰岛素受体（IR）在癌症中日益凸显的作用。多项流行病学研究表明，以高胰岛素血症为特征的胰岛素抵抗状态与多种恶性肿瘤风险增加相关，包括乳腺癌、前列腺癌、结肠癌和肾癌。近期数据阐明了IR参与癌症的一些分子机制。首先，IR在多种人类恶性肿瘤中过度表达。有趣的是，两种IR亚型之一（IR-A）在癌症中尤其过度表达。IR-A是胎儿期的IR亚型，其独特之处在于不仅能结合胰岛素，还能结合IGF-II。其次，IR与同源的IGF-IR形成杂合受体，IGF-IR在癌症中也通常过度表达。这些含有IR-A半体的杂合受体具有广泛的结合特异性，因为它们能结合IGF-I、IGF-II和胰岛素。通过与杂合受体结合，胰岛素可能刺激特定的IGF-IR信号通路。因此，IR-A的过度表达是癌症中IGF系统过度激活的主要机制。这些发现可能对常见人类恶性肿瘤的预防和治疗都具有重要意义。它们强调了这样一个概念，即与胰岛素抵抗和肥胖相关的高胰岛素血症应通过生活方式改变和/或药物治疗来处理，以避免癌症风险增加。因此，IR-A亚型和杂合受体应被视为新型抗癌疗法的潜在分子靶点。
