Targeting SphK1 as a new strategy against cancer.
Targeting SphK1 as a new strategy against cancer.
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DOI：
10.2174/138945008785132402
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发表时间：
2008-08
影响因子：
3.2
通讯作者：
Spiegel S
中科院分区：
文献类型：
--
作者：
Shida D;Takabe K;Kapitonov D;Milstien S;Spiegel S
鞘脂代谢物在许多基本的生物过程中扮演着重要的角色。其中，鞘氨醇-1-磷酸（S1P）促进细胞存活和增殖，而神经酰胺和鞘氨醇则诱导细胞生长阻滞和凋亡。这些具有相反功能的鞘脂在细胞内可以相互转换，这表明它们之间的微妙平衡可以决定细胞的命运。鞘氨醇激酶（SphKs）催化鞘氨醇磷酸化为S1P，是这种平衡的关键调节因子。在这两种已确定的SphKs中，鞘氨酸激酶1型（SphK1）已被证明调节癌症进展的各种重要过程，这将是本综述的重点，因为对SphK2的生物学功能知之甚少，特别是在癌症中。SphK1在各种类型的癌症中过表达，SphK1的上调与肿瘤血管生成和对放疗和化疗的耐药性有关。许多生长因子通过其酪氨酸激酶受体（RTKs）刺激SphK1，导致S1P快速增加。这种S1P反过来可以激活S1P受体及其下游信号传导。相反，S1P受体的激活可以诱导多种rtk的反激活。因此，SphK1可能在S1P受体RTK扩增环中发挥重要作用。在这里，我们回顾了SphK1在肿瘤发生、激素治疗、化疗耐药以及作为预后标志物中的作用。我们还将回顾SphK抑制剂在体外、动物体内和一些临床试验中的作用研究，并强调SphK1作为癌症治疗新靶点的潜力。
Sphingolipid metabolites have emerged as critical players in a number of fundamental biological processes. Among them, sphingosine-1-phosphate (S1P) promotes cell survival and proliferation, in contrast to ceramide and sphingosine, which induce cell growth arrest and apoptosis. These sphingolipids with opposing functions are interconvertible inside cells, suggesting that a finely tuned balance between them can determine cell fate. Sphingosine kinases (SphKs), which catalyze the phosphorylation of sphingosine to S1P, are critical regulators of this balance. Of the two identified SphKs, sphingosine kinase type 1 (SphK1) has been shown to regulate various processes important for cancer progression and will be the focus of this review, since much less is known of biological functions of SphK2, especially in cancer. SphK1 is overexpressed in various types of cancers and upregulation of SphK1 has been associated with tumor angiogenesis and resistance to radiation and chemotherapy. Many growth factors, through their tyrosine kinase receptors (RTKs), stimulate SphK1 leading to a rapid increase in S1P. This S1P in turn can activate S1P receptors and their downstream signaling. Conversely, activation of S1P receptors can induce transactivation of various RTKs. Thus, SphK1 may play important roles in S1P receptor RTK amplification loops. Here we review the role of SphK1 in tumorigenesis, hormonal therapy, chemotherapy resistance, and as a prognostic marker. We will also review studies on the effects of SphK inhibitors in cells in vitro and in animals in vivo and in some clinical trials and highlight the potential of SphK1 as a new target for cancer therapeutics.