Adipose Triglyceride Lipase Loss Promotes a Metabolic Switch in A549 Non–Small Cell Lung Cancer Cell Spheroids

Honeder, Sophie; Tomin, Tamara; Nebel, Laura; Gindlhuber, Juergen; Fritz-Wallace, Katarina; Schinagl, Maximilian; Heininger, Christoph; Schittmayer, Matthias; Ghaffari-Tabrizi-Wizsy, Nassim; Birner‐Gruenberger, Ruth

doi:10.1016/j.mcpro.2021.100095

Cited by 12 publications

(13 citation statements)

References 64 publications

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“… 66 − 68 A very recent study has reported that loss of ATGL function causes a pro-Warburg effect in lung cancer cell spheroids but not in two-dimensional (2D) cell cultures. 69 These studies indicate a tumor-suppressive function of ATGL. Conversely, other studies have suggested that elevated ATGL levels promote tumorigenesis of non-small-cell lung carcinomas and colon cancer cells.…”

Section: Discussionmentioning

confidence: 85%

Small-Molecule Inhibitors Targeting Lipolysis in Human Adipocytes

et al. 2022

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Chronically elevated circulating fatty acid levels promote lipid accumulation in nonadipose tissues and cause lipotoxicity. Adipose triglyceride lipase (ATGL) critically determines the release of fatty acids from white adipose tissue, and accumulating evidence suggests that inactivation of ATGL has beneficial effects on lipotoxicity-driven disorders including insulin resistance, steatohepatitis, and heart disease, classifying ATGL as a promising drug target. Here, we report on the development and biological characterization of the first small-molecule inhibitor of human ATGL. This inhibitor, designated NG-497, selectively inactivates human and nonhuman primate ATGL but not structurally and functionally related lipid hydrolases. We demonstrate that NG-497 abolishes lipolysis in human adipocytes in a dose-dependent and reversible manner. The combined analysis of mouse- and human-selective inhibitors, chimeric ATGL proteins, and homology models revealed detailed insights into enzyme–inhibitor interactions. NG-497 binds ATGL within a hydrophobic cavity near the active site. Therein, three amino acid residues determine inhibitor efficacy and species selectivity and thus provide the molecular scaffold for selective inhibition.

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Section: Discussionmentioning

confidence: 85%

Small-Molecule Inhibitors Targeting Lipolysis in Human Adipocytes

et al. 2022

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“…Compared to 2D cultured cells, the metabolic profile of 3D cultured ATGL-KO A549 cells and their microenvironment more closely resembled the actual situation in vivo (9).…”

Section: Lung Cancermentioning

confidence: 91%

“…The reason for this inconsistent result at the cellular and animal level may be the difference in the microenvironment in which the tumor cells are located. Compared to 2D cultured cells, the metabolic profile of 3D cultured ATGL-KO A549 cells and their microenvironment more closely resembled the actual situation in vivo ( 9 ).…”

Section: Different Roles Of Atgl In Tumorsmentioning

confidence: 96%

“…In cancer cells, all of these proteins are altered to varying degrees, especially ATGL. Intracellular phosphorylated lipases break down triglycerides ( 8 ) stored in LDs to release free fatty acids (FFAs) ( 9 ) involved in intracellular energy metabolism and signal transduction. These lipases include ATGL ( 10 ), hormone-sensitive lipase (HSL), and monoacylglycerol lipase (MGL).…”

Section: Introductionmentioning

confidence: 99%

“…Similarly, decreased levels of ATGL gene expression have been associated with lower survival rates in patients with cervical and gastric cancers. However, in some cancers, ATGL has a promotive effect on tumor progression (9,(19)(20)(21). Therefore, the role of ATGL in tumor cells is uncertain, and it might depend on the type of tumor and the environment in which the tumorigenesis is located.…”

Section: Introductionmentioning

confidence: 99%

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Recent Advances on the Role of ATGL in Cancer

et al. 2022

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The hypoxic state of the tumor microenvironment leads to reprogramming lipid metabolism in tumor cells. Adipose triglyceride lipase, also known as patatin-like phospholipase= domain-containing protein 2 and Adipose triglyceride lipase (ATGL), as an essential lipid metabolism-regulating enzyme in cells, is regulated accordingly under hypoxia induction. However, studies revealed that ATGL exhibits both tumor-promoting and tumor-suppressing effects, which depend on the cancer cell type and the site of tumorigenesis. For example, elevated ATGL expression in breast cancer is accompanied by enhanced fatty acid oxidation (FAO), enhancing cancer cells’ metastatic ability. In prostate cancer, on the other hand, tumor activity tends to be negatively correlated with ATGL expression. This review outlined the regulation of ATGL-mediated lipid metabolism pathways in tumor cells, emphasizing the Hypoxia-inducible factors 1 (HIF-1)/Hypoxia-inducible lipid droplet-associated (HIG-2)/ATGL axis, peroxisome proliferator-activated receptor (PPAR)/G0/G1 switch gene 2 (G0S2)/ATGL axis, and fat-specific protein 27 (FSP-27)/Early growth response protein 1 (EGR-1)/ATGL axis. In the light of recent research on different cancer types, the role of ATGL on tumorigenesis, tumor proliferation, and tumor metastasis was systemically reviewed.

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Lipid droplets provide metabolic flexibility for cancer progression

Safi,

Menéndez,

Pol

2024

FEBS Letters

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A hallmark of cancer cells is their remarkable ability to efficiently adapt to favorable and hostile environments. Due to a unique metabolic flexibility, tumor cells can grow even in the absence of extracellular nutrients or in stressful scenarios. To achieve this, cancer cells need large amounts of lipids to build membranes, synthesize lipid‐derived molecules, and generate metabolic energy in the absence of other nutrients. Tumor cells potentiate strategies to obtain lipids from other cells, metabolic pathways to synthesize new lipids, and mechanisms for efficient storage, mobilization, and utilization of these lipids. Lipid droplets (LDs) are the organelles that collect and supply lipids in eukaryotes and it is increasingly recognized that the accumulation of LDs is a new hallmark of cancer cells. Furthermore, an active role of LD proteins in processes underlying tumorigenesis has been proposed. Here, by focusing on three major classes of LD‐resident proteins (perilipins, lipases, and acyl‐CoA synthetases), we provide an overview of the contribution of LDs to cancer progression and discuss the role of LD proteins during the proliferation, invasion, metastasis, apoptosis, and stemness of cancer cells.

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Adipose Triglyceride Lipase Loss Promotes a Metabolic Switch in A549 Non–Small Cell Lung Cancer Cell Spheroids

Cited by 12 publications

References 64 publications

Small-Molecule Inhibitors Targeting Lipolysis in Human Adipocytes

Small-Molecule Inhibitors Targeting Lipolysis in Human Adipocytes

Recent Advances on the Role of ATGL in Cancer

Lipid droplets provide metabolic flexibility for cancer progression

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