CNRS, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France; Université de Toulouse, Toulouse, France.
Adv Cancer Res. 2013;117:117-41. doi: 10.1016/B978-0-12-394274-6.00005-4.
Hypoxia, defined as a poor oxygenation, has been long recognized as a hallmark of solid tumors and a negative prognostic factor for response to therapeutics and survival of patients. Cancer cells have evolved biochemical mechanisms that allow them to react and adapt to hypoxia. At the cellular level, this adaptation is under the control of two related transcription factors, HIF-1 and HIF-2 (hypoxia-inducible factor), that respond rapidly to decreased oxygen levels to activate the expression of a broad range of genes promoting neoangiogenesis, glycolysis, metastasis, increased tumor growth, and resistance to treatments. Recent studies have identified the sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) signaling pathway-which elicits various cellular processes including cell proliferation, cell survival, or angiogenesis-as a new regulator of HIF-1 or HIF-2 activity. In this review, we will focus on how the inhibition/neutralization of the SphK1/S1P signaling could be exploited for cancer therapy.
缺氧，定义为氧气不足，长期以来一直被认为是实体瘤的标志，也是治疗反应和患者生存的预后不良因素。癌细胞已经进化出了生化机制，使它们能够对缺氧做出反应并适应。在细胞水平上，这种适应受两个相关的转录因子 HIF-1 和 HIF-2（缺氧诱导因子）的控制，它们对氧气水平的降低迅速做出反应，激活一系列促进新生血管生成、糖酵解、转移、肿瘤生长增加和治疗耐药性的基因的表达。最近的研究表明，鞘氨醇激酶 1/鞘氨醇 1-磷酸（SphK1/S1P）信号通路——引发包括细胞增殖、细胞存活或血管生成在内的各种细胞过程——是 HIF-1 或 HIF-2 活性的新调节剂。在这篇综述中，我们将重点介绍抑制/中和 SphK1/S1P 信号通路如何被用于癌症治疗。
