Loss of adipose triglyceride lipase is associated with human cancer and induces mouse pulmonary neoplasia

// Wael Al-Zoughbi 1 , Martin Pichler 2 , Gregor Gorkiewicz 1 , Barbara Guertl-Lackner 1 , Johannes Haybaeck 1 , Stephan W. Jahn 1 , Carolin Lackner 1 , Bernadette Liegl-Atzwanger 1 , Helmut Popper 1 , Silvia Schauer 1 , Elisa Nusshold 1 , Alida S. D. Kindt 3 , Zlatko Trajanoski 3 , Michael R. Speicher 4 , Guenther Haemmerle 5 , Robert Zimmermann 5 , Rudolf Zechner 5 , Paul W. Vesely 1,5 and Gerald Hoefler 1 1 Institute of Pathology, Medical University of Graz, Graz, Austria 2 Division of Oncology, Medical University of Graz, Graz, Austria 3 Biocenter, Division of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria 4 Institute of Human Genetics, Medical University of Graz, Graz, Austria 5 Institute of Molecular Biosciences, University of Graz, Graz, Austria Correspondence to: Paul W. Vesely, email: // Gerald Hoefler, email: // Keywords : adipose triglyceride lipase, cancer metabolism, lipolysis, diagnostic marker Received : November 12, 2015 Accepted : April 02, 2016 Published : May 17, 2016 Abstract Metabolic reprogramming is a hallmark of cancer. Understanding cancer metabolism is instrumental to devise innovative therapeutic approaches. Anabolic metabolism, including the induction of lipogenic enzymes, is a key feature of proliferating cells. Here, we report a novel tumor suppressive function for adipose triglyceride lipase (ATGL), the rate limiting enzyme in the triglyceride hydrolysis cascade. In immunohistochemical analysis, non-small cell lung cancers, pancreatic adenocarcinoma as well as leiomyosarcoma showed significantly reduced levels of ATGL protein compared to corresponding normal tissues. The ATGL gene was frequently deleted in various forms of cancers. Low levels of ATGL mRNA correlated with significantly reduced survival in patients with ovarian, breast, gastric and non-small cell lung cancers. Remarkably, pulmonary neoplasia including invasive adenocarcinoma developed spontaneously in mice lacking ATGL pointing to an important role for this lipase in controlling tumor development. Loss of ATGL, as detected in several forms of human cancer, induces spontaneous development of pulmonary neoplasia in a mouse model. Our results, therefore, suggest a novel tumor suppressor function for ATGL and contribute to the understanding of cancer metabolism. We propose to evaluate loss of ATGL protein expression for the diagnosis of malignant tumors. Finally, modulation of the lipolytic pathway may represent a novel therapeutic approach in the treatment of human cancer.