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

Wael Al-Zoughbi,Johannes Haybaeck,Michael R Speicher,Martin Pichler,Silvia Schauer,Zlatko Trajanoski,Stephan W Jahn,Guenther Haemmerle,Elisa Nusshold,Helmut Popper,Barbara Guertl-Lackner,Alida S D Kindt,Rudolf Zechner,Paul W Vesely,Carolin Lackner,Bernadette Liegl-Atzwanger,Robert Zimmermann,Gerald Hoefler,Gregor Gorkiewicz

doi:10.18632/oncotarget.9418

Wael Al-Zoughbi, Johannes Haybaeck + Show 17 more

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https://doi.org/10.18632/oncotarget.9418

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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.

Highlights

Altered metabolism is regarded a hallmark in the malignant transformation of cells [1,2,3]
When we examined adipose triglyceride lipase (ATGL) protein distribution in normal human adult tissues using immunohistochemical analysis, we observed an inverse correlation between ATGL protein levels and tissue proliferative capacity (Supplementary Figure 1, B)
These data indicate that ATGL expression is reduced or lost in non-small cell lung cancer and other types of malignancies suggesting that cancer cells, similar to fetal tissues, obtain the required energy for homeostasis through glucose and glutamine metabolism rather than from fatty acids (FA) beta-oxidation

Summary

Introduction

Altered metabolism is regarded a hallmark in the malignant transformation of cells [1,2,3]. Specific adaptations in anabolic pathways supply rapidly proliferating cells with building blocks needed to produce nucleic acids, proteins and lipids, driving the formation of biomass [2, 4, 5]. Other metabolic switches in the course of www.impactjournals.com/oncotarget malignant transformation include alterations of citrate cycle enzyme activities, anabolic amino acid pathways, nucleic acids synthesis and lipid metabolism [1, 2, 4, 5, 8]. Since proliferating cancer cells require high amounts of lipids to build up biomembranes, they exhibit high rates of de novo lipogenesis accompanied by increased expression of lipogenic enzymes such as fatty acid synthase [9,10,11,12,13]. Detailed information on the catabolic arm of lipid metabolism during malignant transformation is lacking; insights into a possible role of lipolytic enzymes in cancer development may lead to the development of innovative therapeutic applications

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