LPA receptor1 antagonists as anticancer agents suppress human lung tumours
LPA receptor1 antagonists as anticancer agents suppress human lung tumours
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LPA 受体 1 拮抗剂作为抗癌药物可抑制人类肺部肿瘤
DOI：
10.1016/j.ejphar.2019.172886
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发表时间：
2020
影响因子：
5
通讯作者：
Alatangaole Damirin
中科院分区：
文献类型：
--
作者：
Pengfei Zhao;ShuangWu;YanLi Yan;Gegentuya Bao;Jing-yuan Pei;Qing Ma;Hong-Ju Sun;Alatangaole Damirin
溶血磷脂酸(LPA)作为一种生物活性脂质，通过激活6种G蛋白偶联的LPA受体(LPA1-6)发挥多种生理和病理作用。我们的初步研究发现，LPA1在肺癌组织中的表达高于癌旁组织，但LPA1在肺癌中的作用尚不清楚。本研究旨在从细胞和动物模型水平阐明LPA1与肺癌行为的关系。我们发现LPA促进了肺癌细胞系(A549)的迁移、增殖和结节形成。LPA1和LPA3在A549细胞中优先表达，LPA1和LPA3拮抗剂Ki16425和LPA1拮抗剂ono7300243完全阻断LPA诱导的作用。LPA1/3过表达和LPA1基因敲除A549细胞的实验进一步验证了上述结果。此外，LPA1过表达和基因敲除A549细胞被用来评估体内荷瘤动物模型和LPA诱导作用的机制。在动物模型中，LPA1过表达可显著增加A549细胞来源的肿瘤体积，而LPA1基因敲除后可显著降低A549细胞来源的肿瘤体积，提示LPA1是体内肿瘤形成的调节因子。我们的结果还表明，LPA1/GI/MAPK/NF-κB通路参与了LPA诱导的A549细胞的致癌作用。因此，靶向LPA1可能是治疗肺癌的一种新策略。
Lysophosphatidic acid (LPA), as a bioactive lipid, plays a variety of physiological and pathological roles viaactivating six types of G-protein-coupled LPA receptors (LPA1–6). Our preliminary study found that LPA1 ishighly expressed in lung cancer tissues compared with paracancerous tissues, but the role of LPA1 in lungcarcinoma is unclear. This study aimed to elucidate the association between LPA1 and lung tumour behaviour atthe cellular and animal model levels. We found that LPA promoted the migration, proliferation and colonyformation of a lung cancer cell line (A549). LPA1 and LPA3 are preferentially expressed in A549 cells, and bothKi16425 (LPA1 and LPA3 antagonist) and ono7300243 (LPA1 antagonist) completely blocked the LPA-induced.actions. These results were further verified by experiments of the LPA1/3 overexpression and LPA1 knockdownA549 cells. Furthermore, LPA1 overexpression and knockdown A549 cells were used to assess the in vivo tumour-bearing animal model and the mechanism underlying LPA-induced actions. In the animal model, A549 cell-derived tumour volume was significantly increased by LPA1 overexpression and significantly decreased by LPA1.knockdown respectively, suggesting that LPA1 is a regulator of in vivo tumour formation. Our results also in-dicated that the LPA1/Gi/MAP kinase/NF-κB pathway is involved in LPA-induced oncogenic actions inA549 cells. Thus, targeting LPA1 may be a novel strategy for treating lung carcinoma.