Targeting the Sphingosine Kinase/Sphingosine-1-Phosphate Signaling Axis in Drug Discovery for Cancer Therapy.
Targeting the Sphingosine Kinase/Sphingosine-1-Phosphate Signaling Axis in Drug Discovery for Cancer Therapy.
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针对鞘氨醇激酶/鞘氨醇-1-磷酸信号轴的癌症治疗药物发现。
DOI：
10.3390/cancers13081898
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发表时间：
2021-04-15
期刊：
影响因子：
5.2
通讯作者：
Hassan MI
中科院分区：
文献类型：
--
作者：
Gupta P;Taiyab A;Hussain A;Alajmi MF;Islam A;Hassan MI
癌症是全球死亡的主要原因。在各种人类恶性肿瘤中经常观察到由人类激酶控制的信号通路的刺激改变。SphK 1（一种脂质激酶）及其代谢产物S1 P的过表达已在各种类型的癌症和代谢紊乱中观察到，使其成为潜在的治疗靶点。在这里，我们讨论了鞘脂代谢沿着的关键酶参与的途径。该综述提供了SphK亚型的全面详细信息，包括其功能作用，激活和参与各种人类恶性肿瘤。还综述了不同SphK抑制剂在临床试验的不同阶段的概述，并可能用作癌症治疗剂。鞘脂代谢产物已成为调节各种生理过程的关键参与者。神经酰胺和鞘氨醇诱导细胞生长停滞和凋亡，而鞘氨醇-1-磷酸（S1 P）促进细胞增殖和存活。在这里，我们提出了一个概述鞘脂代谢和各种鞘脂代谢产物的区室化。此外，鞘脂变阻器，神经酰胺和S1 P之间的精细代谢平衡，进行了讨论。鞘氨醇激酶（SphK）催化鞘氨醇合成S1 P并调节几种细胞过程，并且被发现基本上参与各种病理生理条件。讨论了SphK异构体的调节和生物学功能。S1 P的功能，沿着其受体，进一步突出。SphK的上调在各种癌症类型中观察到，并且还与癌症患者的放射性和化学抗性以及预后不良有关。SphK/S1 P信号轴在人类病理学及其抑制的影响进行了详细讨论。总体而言，这篇综述从多个角度强调了SphK/S1 P信号轴的当前研究结果，包括其功能作用，激活机制，参与各种人类恶性肿瘤，以及可能用于癌症治疗的抑制剂分子。
Cancer is the prime cause of death globally. The altered stimulation of signaling pathways controlled by human kinases has often been observed in various human malignancies. The over-expression of SphK1 (a lipid kinase) and its metabolite S1P have been observed in various types of cancer and metabolic disorders, making it a potential therapeutic target. Here, we discuss the sphingolipid metabolism along with the critical enzymes involved in the pathway. The review provides comprehensive details of SphK isoforms, including their functional role, activation, and involvement in various human malignancies. An overview of different SphK inhibitors at different phases of clinical trials and can potentially be utilized as cancer therapeutics has also been reviewed. Sphingolipid metabolites have emerged as critical players in the regulation of various physiological processes. Ceramide and sphingosine induce cell growth arrest and apoptosis, whereas sphingosine-1-phosphate (S1P) promotes cell proliferation and survival. Here, we present an overview of sphingolipid metabolism and the compartmentalization of various sphingolipid metabolites. In addition, the sphingolipid rheostat, a fine metabolic balance between ceramide and S1P, is discussed. Sphingosine kinase (SphK) catalyzes the synthesis of S1P from sphingosine and modulates several cellular processes and is found to be essentially involved in various pathophysiological conditions. The regulation and biological functions of SphK isoforms are discussed. The functions of S1P, along with its receptors, are further highlighted. The up-regulation of SphK is observed in various cancer types and is also linked to radio- and chemoresistance and poor prognosis in cancer patients. Implications of the SphK/S1P signaling axis in human pathologies and its inhibition are discussed in detail. Overall, this review highlights current findings on the SphK/S1P signaling axis from multiple angles, including their functional role, mechanism of activation, involvement in various human malignancies, and inhibitor molecules that may be used in cancer therapy.
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鞘氨醇激酶和1-磷酸盐受体：心血管系统中的信号传导和作用。
影响因子：
5.6
作者：
Cannavo A;Liccardo D;Komici K;Corbi G;de Lucia C;Femminella GD;Elia A;Bencivenga L;Ferrara N;Koch WJ;Paolocci N;Rengo G
通讯作者：
Rengo G
影响因子：
7.3
作者：
Baek DJ;MacRitchie N;Anthony NG;Mackay SP;Pyne S;Pyne NJ;Bittman R
通讯作者：
Bittman R
影响因子：
64.5
作者：
Chipuk JE;McStay GP;Bharti A;Kuwana T;Clarke CJ;Siskind LJ;Obeid LM;Green DR
通讯作者：
Green DR
影响因子：
4.6
作者：
Aoki M;Aoki H;Ramanathan R;Hait NC;Takabe K
通讯作者：
Takabe K
影响因子：
3.5
作者：
Canals, Daniel;Mormeneo, David;Delgado, Antonio
通讯作者：
Delgado, Antonio