Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz

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SHR Neuro Krebs Kardio Lipid

Tomin, T; Fritz, K; Gindlhuber, J; Waldherr, L; Pucher, B; Thallinger, GG; Nomura, DK; Schittmayer, M; Birner-Gruenberger, R.
Deletion of Adipose Triglyceride Lipase links triacylglycerol accumulation to a more aggressive phenotype in A549 lung carcinoma cells.
J Proteome Res. 2018;
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Autor/innen der Med Uni Graz:
Birner-Grünberger Ruth
Fritz Katarina
Gindlhuber Jürgen
Schittmayer-Schantl Matthias
Tomin Tamara
Waldherr Linda

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Plum Analytics:
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 where 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 and reversible by reintroduction of ATGL. Moreover, pharmacological inhibition of murine ATGL in LLC1/LL2 Lewis lung carcinoma cells and AML12 hepatocytes reproduced the observed phenotype of SRC activation and increased migratory potential suggesting a general link between loss of ATGL activity, accumulation of lipids, activation of SRC and increased migration. 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.

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