Therapeutic Targeting of the Secreted Lysophospholipase D Autotaxin Suppresses Tuberous Sclerosis Complex-Associated Tumorigenesis
Therapeutic Targeting of the Secreted Lysophospholipase D Autotaxin Suppresses Tuberous Sclerosis Complex-Associated Tumorigenesis
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DOI：
10.1158/0008-5472.can-19-2884
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发表时间：
2020-07-01
期刊：
影响因子：
11.2
通讯作者：
Priolo, Carmen
中科院分区：
文献类型：
--
作者：
Feng, You;Mischler, William J.;Priolo, Carmen
结节性硬化症（TSC）是一种常染色体显性遗传病，以多器官错构瘤为特征，包括肾血管平滑肌脂肪瘤和肺淋巴管平滑肌瘤病（LAM）。TSC2缺乏导致mTOR复合物1 （mTORC1）的过度激活，mTORC1是细胞生长和代谢的主要调节因子。当TSC2缺失时，磷脂代谢失调，导致TSC2缺失的肿瘤细胞产生溶血磷脂酰胆碱（LPC）物种增加。LPC是分泌的溶血磷脂酶D autotaxin （ATX）的主要底物，ATX产生两种生物活性脂质，溶血磷脂酸（LPA）和鞘磷脂- 1-磷酸（S1P）。我们在这里报道，与TSC2补充细胞相比，ATX在人肾血管平滑肌脂肪瘤来源的TSC2缺陷细胞中的表达上调。通过临床开发的化合物GLPG1690抑制ATX在体外和体内可抑制tsc2缺失相关的致癌性，并诱导tsc2缺陷细胞凋亡。GLPG1690抑制AKT和ERK1/2信号通路，深刻影响这些细胞的转录组，同时诱导TSC2 add-back细胞的少量基因表达变化。rna测序研究揭示了LPA和S1P的转录组特征，表明LPA/S1P介导了TSC脂质组的重编程。此外，在GLPG1690处理的人tsc2缺陷细胞中，补充I.PA或SIP可挽救增殖和活力、中性脂质含量以及AKT或ERKI/2信号。重要的是，与正常肾脏相比，tsc相关的肾血管平滑肌脂肪瘤具有更高的LPA受体1和SIP受体3的表达。这些研究增加了我们对tsc2缺陷细胞代谢的理解，为TSC和LAM提供了新的潜在治疗机会。意义：本研究发现ATX- lpa /S1P通路的激活是TSC2缺失时代谢失调的一种新模式，强调了ATX在TSC2缺陷细胞适应性和TSC肿瘤发生中的关键作用。
Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by multiorgan hamartomas, including renal angiomyolipomas and pulmonary lymphangioleiomyomatosis (LAM). TSC2 deficiency leads to hyperactivation of mTOR Complex 1 (mTORC1), a master regulator of cell growth and metabolism. Phospholipid metabolism is dysregulated upon TSC2 loss, causing enhanced production of lysophosphatidylcholine (LPC) species by TSC2-deficient tumor cells. LPC is the major substrate of the secreted lysophospholipase D autotaxin (ATX), which generates two bioactive lipids, lysophosphatidic acid (LPA) and sphingosine- 1-phosphate (S1P). We report here that ATX expression is upregulated in human renal angiomyolipoma-derived TSC2-deficient cells compared with TSC2 add-back cells. Inhibition of ATX via the clinically developed compound GLPG1690 suppressed TSC2-loss associated oncogenicity in vitro and in vivo and induced apoptosis in TSC2-deficient cells. GLPG1690 suppressed AKT and ERK1/2 signaling and profoundly impacted the transcriptome of these cells while inducing minor gene expression changes in TSC2 add-back cells. RNA-sequencing studies revealed transcriptomic signatures of LPA and S1P, suggesting an LPA/S1P-mediated reprogramming of the TSC lipidome. In addition, supplementation of I.PA or SIP rescued proliferation and viability, neutral lipid content, and AKT or ERKI/2 signaling in human TSC2-deficient cells treated with GLPG1690. Importantly, TSC-associated renal angiomyolipomas have higher expression of LPA receptor 1 and SIP receptor 3 compared with normal kidney. These studies increase our understanding of TSC2-deficient cell metabolism, leading to novel potential therapeutic opportunities for TSC and LAM.Significance: This study identifies activation of the ATX-LPA/S1P pathway as a novel mode of metabolic dysregulation upon TSC2 loss, highlighting critical roles for ATX in TSC2-deficient cell fitness and in TSC tumorigenesis.