Koh Mei Yee, Spivak-Kroizman Taly R, Powis Garth
Department of Experimental Therapeutics, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Recent Results Cancer Res. 2010;180:15-34. doi: 10.1007/978-3-540-78281-0_3.
Most solid tumors develop regions of hypoxia as they grow and outstrip their blood supply. In order to survive in the stressful hypoxic environment, tumor cells have developed a coordinated set of responses orchestrating their adaptation to hypoxia. The outcomes of the cellular responses to hypoxia are aggressive disease, resistance to therapy, and decreased patient survival. A critical mediator of the hypoxic response is the transcription factor hypoxia-inducible factor 1 (HIF-1) that upregulates expression of proteins that promote angiogenesis, anaerobic metabolism, and many other survival pathways. Regulation of HIF-1alpha, a component of the HIF-1 heterodimer, occurs at multiple levels including translation, degradation, and transcriptional activation, and serves as a testimony to the central role of HIF-1. Studies demonstrating the importance of HIF-1alpha expression for tumor survival have made HIF-1alpha an attractive target for cancer therapy. The growing l.ist of pharmacological inhibitors of HIF-1 and their varied targets mirrors the complex molecular mechanisms controlling HIF-1. In this chapter, we summarize recent findings regarding the regulation of HIF-1alpha and the progress made in identifying new therapeutic agents that inhibit HIF-1alpha.
大多数实体瘤在生长过程中会形成缺氧区域，因为它们的生长超过了血液供应。为了在应激性缺氧环境中生存，肿瘤细胞已经形成了一套协调的反应机制，以协调它们对缺氧的适应。细胞对缺氧反应的结果是疾病进展、对治疗产生抗性以及患者生存率降低。缺氧反应的一个关键介质是转录因子缺氧诱导因子1（HIF-1），它上调促进血管生成、无氧代谢和许多其他生存途径的蛋白质的表达。HIF-1异二聚体的一个组成部分HIF-1α的调节发生在多个水平，包括翻译、降解和转录激活，这证明了HIF-1的核心作用。证明HIF-1α表达对肿瘤生存重要性的研究使HIF-1α成为癌症治疗的一个有吸引力的靶点。HIF-1的药理抑制剂及其不同靶点的清单不断增加，这反映了控制HIF-1的复杂分子机制。在本章中，我们总结了关于HIF-1α调节的最新发现以及在鉴定抑制HIF-1α的新治疗药物方面取得的进展。
