Department of Biochemistry, University of Alberta, Edmonton T6G 2S2, Canada; Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton T6G 2S2, Canada.
Department of Biochemistry, University of Alberta, Edmonton T6G 2S2, Canada; Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton T6G 2S2, Canada; Discipline of Surgery, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador A1B 3V6, Canada.
Biochim Biophys Acta Mol Cell Biol Lipids. 2020 Aug;1865(8):158716. doi: 10.1016/j.bbalip.2020.158716. Epub 2020 Apr 16.
Autotaxin (ATX) is a secreted enzyme that hydrolyzes lysophosphatidylcholine to produce lysophosphatidate (LPA), which signals through six G-protein coupled receptors (GPCRs). Signaling through LPA is terminated by its degradation by a family of three lipid phosphate phosphatases (LPPs). LPP1 also attenuates signaling downstream of the activation of LPA receptors and some other GPCRs. The ATX-LPA axis mediates a plethora of activities such as cell proliferation, survival, migration, angiogenesis and inflammation, which perform an important role in facilitating wound healing. This wound healing response is hijacked by cancers where there is decreased expression of LPP1 and LPP3 and increased expression of ATX. This maladaptive regulation of LPA signaling also causes chronic inflammation, which has been recognized as one of the hallmarks in cancer. The increased LPA signaling promotes cell survival and migration and attenuates apoptosis, which stimulates tumor growth and metastasis. The wound healing functions of increased LPA signaling also protect cancer cells from effects of chemotherapy and radiotherapy. In this review, we will summarize knowledge of the ATX-LPA axis and its role in the development of resistance to chemotherapy and radiotherapy. We will also offer insights for developing strategies of targeting ATX-LPA axis as a novel part of cancer treatment. This article is part of a Special Issue entitled Lysophospholipids and their receptors: New data and new insights into their function edited by Susan Smyth, Viswanathan Natarajan and Colleen McMullen.
自分泌酶（Autotaxin，ATX）是一种分泌型酶，能够将溶血磷脂酰胆碱（lysophosphatidylcholine）水解为溶血磷脂酸（lysophosphatidate，LPA），后者通过六种 G 蛋白偶联受体（G-protein coupled receptors，GPCRs）发挥信号转导作用。LPA 的信号转导可通过其被三种脂质磷酸酶（lipid phosphate phosphatases，LPPs）家族成员降解而终止。LPP1 还可减弱 LPA 受体和其他一些 GPCR 激活后的信号转导。ATX-LPA 轴介导了大量的生物学活动，如细胞增殖、存活、迁移、血管生成和炎症等，这些活动在促进伤口愈合中发挥着重要作用。在癌症中，这种伤口愈合反应被劫持，其表现为 LPP1 和 LPP3 的表达减少，以及 ATX 的表达增加。LPA 信号转导的这种适应性失调还会导致慢性炎症，这已被认为是癌症的一个标志。增加的 LPA 信号转导促进细胞存活和迁移，并抑制细胞凋亡，从而刺激肿瘤生长和转移。增加的 LPA 信号转导的伤口愈合功能还可以保护癌细胞免受化疗和放疗的影响。在这篇综述中，我们将总结 ATX-LPA 轴及其在化疗和放疗耐药发展中的作用的相关知识。我们还将提供有关靶向 ATX-LPA 轴作为癌症治疗新方法的见解。本文是 Susan Smyth、Viswanathan Natarajan 和 Colleen McMullen 主编的题为“溶血磷脂及其受体：功能的新数据和新见解”的特刊的一部分。
