Alteration of Cellular Energy Metabolism through LPAR2-Axin2 Axis in Gastric Cancer.
Alteration of Cellular Energy Metabolism through LPAR2-Axin2 Axis in Gastric Cancer.
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DOI：
10.3390/biom12121805
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发表时间：
2022-12-02
期刊：
影响因子：
5.5
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中科院分区：
文献类型：
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溶血磷脂酸（LPA）是一种多功能的内源性磷脂，通过G蛋白偶联受体在细胞内稳态和癌细胞恶性行为中起着至关重要的作用。然而，LPA在β-catenin介导的胃癌中的作用尚不清楚。在此，我们注意到LPA 2在人胃癌组织中的高表达，并且LPA处理显著增加了人胃癌细胞的增殖、迁移和侵袭。我们的生化实验结果表明，LPA暴露增加了β-catenin的表达及其核定位，增加了糖原合成酶激酶3β（GSK-3β）的磷酸化，降低了Axin 2的表达，并增加了β-catenin信号通路靶基因的表达。LPA 2受体（LPAR 2）拮抗剂显著降低了LPA诱导的β-连环蛋白（主要信号传导事件）的核定位。在胃癌细胞系中，LPAR 2的敲低强烈地降低了LPA诱导的β-连环蛋白活性。LPA暴露通过氧化磷酸化和糖酵解增加ATP产生，并且这种作用通过添加LPAR 2拮抗剂和XAV 393而消除，XAV 393稳定Axin并抑制β-连环蛋白信号传导途径。基于我们的研究结果，LPA通过β-catenin信号通路以及分别通过LPAR 2受体和Axin 2的能量代谢失调促进胃癌发生和发展的可能性，为胃癌的机制和可能的治疗靶点提供了新的见解。
Lysophosphatidic acid (LPA), a multifunctional endogenous phospholipid, plays a vital role in cellular homeostasis and the malignant behavior of cancer cells through G-protein-coupled receptors. However, the role of LPA in β-catenin-mediated gastric cancer is unknown. Here, we have noted the high expression of LPAR2 in human gastric cancer tissues, and that LPA treatment significantly increased the proliferation, migration, and invasion of human gastric cancer cells. Results from our biochemical experiments showed that an LPA exposure increased the expression of β-catenin and its nuclear localization, increased the phosphorylation of glycogen synthase kinase 3β (GSK-3β), decreased the expression of Axin2, and increased the expression of the target genes of the β-catenin signaling pathway. The LPA2 receptor (LPAR2) antagonist significantly reduced the LPA-induced nuclear localization of β-catenin, the primary signaling event. The knockdown of LPAR2 in the gastric cancer cell lines robustly reduced the LPA-induced β-catenin activity. An LPA exposure increased the ATP production by both oxidative phosphorylation and glycolysis, and this effect was abrogated with the addition of an LPAR2 antagonist and XAV393, which stabilizes the Axin and inhibits the β-catenin signaling pathway. Based on our findings, the possibility that LPA contributes to gastric cancer initiation and progression through the β-catenin signaling pathway as well as by the dysregulation of the energy metabolism via the LPAR2 receptor and Axin2, respectively, provides a novel insight into the mechanism of and possible therapeutic targets of gastric cancer.
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影响因子：
4
作者：
Abbruzzese, Genevieve;Gorny, Anne-Kathrin;Alfandari, Dominique
通讯作者：
Alfandari, Dominique
影响因子：
11.4
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DOI：
10.1152/ajpgi.00321.2010
发表时间：
2010-11-01
影响因子：
4.5
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影响因子：
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作者：
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影响因子：
64.5
作者：
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Sabatini, David M.