Jiang Bing-Hua, Liu Ling-Zhi
Lab. of Reproductive Medicine, Cancer Center, Nanjing Medical University, Nanjing 210029, Jiangsu, China.
Curr Cancer Drug Targets. 2008 Feb;8(1):19-26. doi: 10.2174/156800908783497122.
AKT is a central signaling molecule in regulating cell survival, proliferation, tumor growth and angiogenesis. Upstream components of AKT signaling pathway such as PI3K, PTEN, and Ras are commonly mutated in many human cancers. Recently it is found that AKT plays an important role in regulating normal vascularization and pathological angiogenesis. Angiogenesis is required for tumor growth and metastasis when tumor reaches more than 1 mm in diameter. This review focuses on the role and potential mechanism of AKT signaling in regulating angiogenesis. Recent studies have shown that AKT activation is necessary and sufficient to regulate VEGF and HIF-1 expression in human cancer cells. VEGF and HIF-1 are potent inducers of angiogenesis. It was found that AKT activation induces VEGF and HIF-1 expression through its two downstream molecules HDM2 and p70S6K1. On the other hand, AKT transmits the upstream signals from growth factors, cytokines, heavy metals, and oncogenes for regulating VEGF and HIF-1 expression in human cancer cells. AKT activation and VEGF expression can be inhibited by different natural compounds used for cancer prevention. Thus, inhibition of AKT and its downstream targets offers a new approach for targeting angiogenesis, which could be important for the development of new cancer therapeutics in the future.
AKT是调节细胞存活、增殖、肿瘤生长和血管生成的核心信号分子。AKT信号通路的上游成分，如PI3K、PTEN和Ras，在许多人类癌症中通常发生突变。最近发现，AKT在调节正常血管生成和病理性血管生成中起重要作用。当肿瘤直径超过1毫米时，血管生成是肿瘤生长和转移所必需的。本综述重点关注AKT信号在调节血管生成中的作用和潜在机制。最近的研究表明，AKT激活对于调节人类癌细胞中的VEGF和HIF-1表达是必要且充分的。VEGF和HIF-1是血管生成的强效诱导剂。研究发现，AKT激活通过其两个下游分子HDM2和p70S6K1诱导VEGF和HIF-1表达。另一方面，AKT传递来自生长因子、细胞因子、重金属和癌基因的上游信号，以调节人类癌细胞中的VEGF和HIF-1表达。用于癌症预防的不同天然化合物可抑制AKT激活和VEGF表达。因此，抑制AKT及其下游靶点为靶向血管生成提供了一种新方法，这对未来新型癌症治疗药物的开发可能具有重要意义。
