Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Al Zoughbi, W.
The Function of Adipose Triglyceride Lipase as a Tumor Suppressor
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2016. pp.
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- Autor*innen der Med Uni Graz:
- Al-Zoughbi Wael
- Betreuer*innen:
- Höfler Gerald
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- Abstract:
- Altered cellular metabolism has been recognized as one of the hallmarks of tumor cells and is emerging as a therapeutic target. Certainly, understanding the metabolic differences between normal and cancer cells is the key for success in utilizing metabolic targets to combat cancer. Unlike specialized cells, cancer cells constitutively exhibit an anabolic form of metabolism including the induction of lipogenic enzymes. Of lipolytic enzymes, only monoglyceride lipase (MGL) has been clearly implicated in human cancer. Here, we report a novel tumor suppressor function for the rate limiting enzyme in the triglyceride hydrolysis cascade, adipose triglyceride lipase (ATGL). ATGL mRNA and ATGL protein levels are significantly downregulated in several human malignant tumors compared to the corresponding normal tissues and reduced ATGL mRNA expression correlates with decreased patients overall survival in at least four types of malignancies. Remarkably, loss of ATGL protein in pancreatic cancers is an early event during tumorigenesis suggesting that there is a selective advantage conferred by losing ATGL. This hypothesis is supported by the finding that loss of ATGL enhances tumor growth and progression in mouse models. Tumor cells in which ATGL is absent exhibit higher proliferation rate in vitro and in vivo, and increased ability to invade and spread. It is possible that ATGL, as a critical enzyme in fat catabolism, regulates and controls –at least in part— anabolic pathways that influence cell proliferation. Besides the growth advantage, tumor cell recognition by the host immune system is severely impaired upon the loss of ATGL. As a result, these cells have additional survival advantage in immune-competent C57BL6 mice compared to immune compromised mice that exhibit severe combined immune deficient phenotype. In fact, escaping the antitumor immune response upon the loss of ATGL might reveal a unique mechanistic link between the cellular triglyceride (TG) catabolism pathway and the adaptive immune response against tumors. Loss of ATGL not only confers growth and survival advantages for tumor cells, but also is sufficient to induce spontaneous bronchoepithelial neoplasias and tumors in lungs of C57BL6 mice, thus revealing a possible role for ATGL in controlling tumor initiation and development. Given that the human ATGL gene – located in the tumor suppressor region 11p15.5 — exhibits high frequency of gene copy number loss in multiple cancer types, the loss of human ATGL gene may be instrumental for the development of human cancers that are associated with alteration in the 11p15.5 chromosomal region. In addition to the reported role of MGL in cancer development and progression, we show that deregulation of the rate limiting enzyme in the catabolic arm of the TG/Fatty acids cycle plays a role in tumorigenesis. Our results identify a novel discrepancy in lipid metabolism between normal and cancer cells, and indicate that the principal enzyme in TG lipolysis, ATGL, is implicated in controlling tumor development, growth and aggressiveness. This study establishes a tumor suppressor function for ATGL and contributes to a better understanding of cancer metabolism.