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

Abstract

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.

Of mice and men: The physiological role of adipose triglyceride lipase (ATGL)

“…Further experiments showed that ATGL upregulation in breast cancer was associated with a tumor microenvironment enriched in adipocytes, leading to a pro-oncogenic lipid network and subsequent invasiveness [ 194 ]. In contrast, pharmacological inhibition of ATGL or ATGL disruption by CRISPR/Cas9 led to a more aggressive phenotype in parallel with increased intracellular TG content of lung cancer cell lines [ 195 ]. This inconsistency of in vitro studies needs further clarification but may be due to different technologies and cancer types used for reducing ATGL activity.…”

Implications of lipid droplets in lung cancer: Associations with drug resistance (Review)

“…The high lipid droplet content in cancer cells may enhance migration. Tomin et al (109) knocked out triglyceride lipase (ATGL) in the lung cancer A549 cells and demonstrated that a large number of lipid droplets was accumulated in the cells. In addition, cellular phospholipids and bioactive lipids (such as lyso-and ether-phospholipids) are also upregulated.…”

“…In addition, cellular phospholipids and bioactive lipids (such as lyso-and ether-phospholipids) are also upregulated. Proteomic data showed that pro-oncogene SRC kinase expression is upregulated, and phosphorylated (p-)SRC (Y416 p-SRC, activated SRC) expression is also increased (109). Lung cancer cells exhibit faster migration rates, suggesting greater tumor aggressiveness (108).…”

Non-Coding and Regulatory RNAs as Epigenetic Remodelers of Fatty Acid Homeostasis in Cancer

“…In fact, inhibitors of this enzyme resulted in the attenuation of cancer cell growth, such as in different lung carcinoma cell lines [ 110 ]. However, other studies reported the downregulation of ATGL protein expression to be linked with several malignant tumors, such as non-small cell lung cancers and pancreatic adenocarcinoma, as well as ovarian and breast tumors [ 111 , 112 , 113 ]. In these cases, the overexpression of ATGL or HSL by direct or indirect therapeutic means, could be detrimental for the patient, due to its association with cachexia, a multifactorial wasting syndrome in oncologic patients characterized by the uncontrolled loss of adipose tissue and muscle mass [ 114 ].…”