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

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.