Deletion of Adipose Triglyceride Lipase Links Triacylglycerol Accumulation to a More-Aggressive Phenotype in A549 Lung Carcinoma Cells,Journal of Proteome Research

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Deletion of Adipose Triglyceride Lipase Links Triacylglycerol Accumulation to a More-Aggressive Phenotype in A549 Lung Carcinoma Cells
Journal of Proteome Research ( IF 3.8 ) Pub Date : 2018-03-07 00:00:00 , DOI: 10.1021/acs.jproteome.7b00782
Tamara Tomin _{1,

2} , Katarina Fritz _{1,

2} , Juergen Gindlhuber _{1,

2} , Linda Waldherr _{1,

2} , Bettina Pucher _{2,

3} , Gerhard G Thallinger _{2,

3} , Daniel K Nomura , Matthias Schittmayer _{1,

2} , Ruth Birner-Gruenberger _{1,

2}

Affiliation

Adipose triglyceride lipase (ATGL) catalyzes the rate limiting step in triacylglycerol breakdown in adipocytes but is expressed in most tissues. The enzyme was shown to be lost in many human tumors, and its loss may play a role in early stages of cancer development. Here, we report that loss of ATGL supports a more-aggressive cancer phenotype in a model system in which ATGL was deleted in A549 lung cancer cells by CRISPR/Cas9. We observed that loss of ATGL led to triacylglycerol accumulation in lipid droplets and higher levels of cellular phospholipid and bioactive lipid species (lyso- and ether-phospholipids). Label-free quantitative proteomics revealed elevated expression of the pro-oncogene SRC kinase in ATGL depleted cells, which was also found on mRNA level and confirmed on protein level by Western blot. Consistently, higher expression of phosphorylated (active) SRC (Y416 phospho-SRC) was observed in ATGL-KO cells. Cells depleted of ATGL migrated faster, which was dependent on SRC kinase activity. We propose that loss of ATGL may thus increase cancer aggressiveness by activation of pro-oncogenic signaling via SRC kinase and increased levels of bioactive lipids.

中文翻译：

脂肪甘油三酯脂肪酶的缺失将甘油三酯的积累与 A549 肺癌细胞中更具侵袭性的表型联系起来

脂肪甘油三酯脂肪酶 (ATGL) 催化脂肪细胞中三酰基甘油分解的限速步骤，但在大多数组织中表达。该酶被证明在许多人类肿瘤中丢失，它的丢失可能在癌症发展的早期阶段发挥作用。在这里，我们报告说 ATGL 的缺失支持了模型系统中更具侵袭性的癌症表型，其中 ATGL 在 A549 肺癌细胞中被 CRISPR/Cas9 删除。我们观察到 ATGL 的损失导致脂滴中的三酰基甘油积累和更高水平的细胞磷脂和生物活性脂质种类（溶血磷脂和醚磷脂）。无标记定量蛋白质组学显示原癌基因 SRC 激酶在 ATGL 耗尽细胞中的表达升高，这也在 mRNA 水平上发现，并通过蛋白质印迹在蛋白质水平上得到证实。一贯地，在 ATGL-KO 细胞中观察到磷酸化（活性）SRC（Y416 磷酸-SRC）的更高表达。耗尽 ATGL 的细胞迁移得更快，这取决于 SRC 激酶活性。我们提出，ATGL 的缺失可能因此通过 SRC 激酶激活促癌信号和增加生物活性脂质水平来增加癌症侵袭性。

更新日期：2018-03-07

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