Sharon M. Louie

Ether lipid generating enzyme AGPS alters the balance of structural and signaling lipids to fuel cancer pathogenicity

Significance Ether lipid levels are higher in tumors, but their specific function in cancer has remained unclear. We show here that the metabolic enzyme alkylglyceronephosphate synthase (AGPS), a critical step in the synthesis of ether lipids, is up-regulated across multiple types of aggressive human cancer cells and primary tumors. Inactivation of AGPS leads to significant impairments in cancer pathogenicity through not only lowering the levels of cellular ether lipids, but also by altering fatty acid, eicosanoid, and glycerophospholipid metabolism, resulting in an overall reduction in the levels of several oncogenic signaling lipids. Aberrant lipid metabolism is an established hallmark of cancer cells. In particular, ether lipid levels have been shown to be elevated in tumors, but their specific function in cancer remains elusive. We show here that the metabolic enzyme alkylglyceronephosphate synthase (AGPS), a critical step in the synthesis of ether lipids, is up-regulated across multiple types of aggressive human cancer cells and primary tumors. We demonstrate that ablation of AGPS in cancer cells results in reduced cell survival, cancer aggressiveness, and tumor growth through altering the balance of ether lipid, fatty acid, eicosanoid, and fatty acid–derived glycerophospholipid metabolism, resulting in an overall reduction in the levels of several oncogenic signaling lipids. Taken together, our results reveal that AGPS, in addition to maintaining ether lipids, also controls cellular utilization of fatty acids, favoring the generation of signaling lipids necessary for promoting the aggressive features of cancer.

Mechanisms linking obesity and cancer.

The incidence of obesity in US adults has been steadily increasing over the past few decades. Many comorbidities associated with obesity have been well-established such as type 2 diabetes and cardiovascular diseases. However, more recently an epidemiological relationship between obesity and the prevalence of a variety of cancers has also been uncovered. The shift of the paradigm surrounding white adipose tissue function from purely an energy storage tissue, to one that has both endocrine and metabolic relevance, has led to several mechanisms implicated in how obesity drives cancer prevalence and cancer deaths. Currently, there are four categories into which these mechanisms fall - increased lipids and lipid signaling, inflammatory responses, insulin resistance, and adipokines. In this review, we examine each of these categories and the mechanisms through which they drive cancer pathogenesis. Understanding the relationship(s) between obesity and cancer and especially the nodal points of control in these cascades will be essential in developing effective therapeutics or interventions for combating this deadly combination. This article is part of a Special Issue entitled Lipid Metabolism in Cancer.

Cancer cells incorporate and remodel exogenous palmitate into structural and oncogenic signaling lipids.

De novo lipogenesis is considered the primary source of fatty acids for lipid synthesis in cancer cells, even in the presence of exogenous fatty acids. Here, we have used an isotopic fatty acid labeling strategy coupled with metabolomic profiling platforms to comprehensively map palmitic acid incorporation into complex lipids in cancer cells. We show that cancer cells and tumors robustly incorporate and remodel exogenous palmitate into structural and oncogenic glycerophospholipids, sphingolipids, and ether lipids. We also find that fatty acid incorporation into oxidative pathways is reduced in aggressive human cancer cells, and instead shunted into pathways for generating structural and signaling lipids. Our results demonstrate that cancer cells do not solely rely on de novo lipogenesis, but also utilize exogenous fatty acids for generating lipids required for proliferation and protumorigenic lipid signaling. This article is part of a special issue entitled Lipid Metabolism in Cancer.

Lysosomal cholesterol activates mTORC1 via an SLC38A9-Niemann-Pick C1 signaling complex

A cholesterol-mTORC1 axis may play a role in metabolic homeostasis in normal and disease states. Lysosomal cholesterol activates mTORC1 The mTORC1 kinase is a master nutrient sensor that governs cellular metabolism. When dysregulated, this kinase drives several human diseases, including cancer and diabetes. Recent work has delineated a pathway through which amino acids regulate mTORC1. In contrast, little is known about how sterols may affect mTORC1 signaling. Castellano et al. provide detailed mechanistic evidence for how cholesterol, derived from the processing of low-density lipoprotein in the lysosomal lumen, drives mTORC1 signaling. They identify the key players that couple lysosomal cholesterol levels to mTORC1 activation. Unexpectedly, the putative amino acid transporter SLC38A9, which is implicated in mTORC1 regulation by arginine, is essential for mTORC1 activation by cholesterol. Furthermore, the authors uncover a physical and functional interaction between SLC38A9 and the major lysosomal cholesterol transporter, Niemann-Pick C1 (NPC1) protein. The SLC38A9-NPC1 complex is key to the ability of mTORC1 to respond to variations in dietary lipid supply. Science, this issue p. 1306 The mechanistic target of rapamycin complex 1 (mTORC1) protein kinase is a master growth regulator that becomes activated at the lysosome in response to nutrient cues. Here, we identify cholesterol, an essential building block for cellular growth, as a nutrient input that drives mTORC1 recruitment and activation at the lysosomal surface. The lysosomal transmembrane protein, SLC38A9, is required for mTORC1 activation by cholesterol through conserved cholesterol-responsive motifs. Moreover, SLC38A9 enables mTORC1 activation by cholesterol independently from its arginine-sensing function. Conversely, the Niemann-Pick C1 (NPC1) protein, which regulates cholesterol export from the lysosome, binds to SLC38A9 and inhibits mTORC1 signaling through its sterol transport function. Thus, lysosomal cholesterol drives mTORC1 activation and growth signaling through the SLC38A9-NPC1 complex.

Metabolic Profiling Reveals PAFAH1B3 as a Critical Driver of Breast Cancer Pathogenicity

Many studies have identified metabolic pathways that underlie cellular transformation, but the metabolic drivers of cancer progression remain less well understood. The Hippo transducer pathway has been shown to confer malignant traits on breast cancer cells. In this study, we used metabolic mapping platforms to identify biochemical drivers of cellular transformation and malignant progression driven through RAS and the Hippo pathway in breast cancer and identified platelet-activating factor acetylhydrolase 1B3 (PAFAH1B3) as a key metabolic driver of breast cancer pathogenicity that is upregulated in primary human breast tumors and correlated with poor prognosis. Metabolomic profiling suggests that PAFAH1B3 inactivation attenuates cancer pathogenicity through enhancing tumor-suppressing signaling lipids. Our studies provide a map of altered metabolism that underlies breast cancer progression and put forth PAFAH1B3 as a critical metabolic node in breast cancer.

Inositol Phosphate Recycling Regulates Glycolytic and Lipid Metabolism That Drives Cancer Aggressiveness

Cancer cells possess fundamentally altered metabolism that supports their pathogenic features, which includes a heightened reliance on aerobic glycolysis to provide precursors for synthesis of biomass. We show here that inositol polyphosphate phosphatase 1 (INPP1) is highly expressed in aggressive human cancer cells and primary high-grade human tumors. Inactivation of INPP1 leads to a reduction in glycolytic intermediates that feed into the synthesis of the oncogenic signaling lipid lysophosphatidic acid (LPA), which in turn impairs LPA signaling and further attenuates glycolytic metabolism in a feed-forward mechanism to impair cancer cell motility, invasiveness, and tumorigenicity. Taken together these findings reveal a novel mode of glycolytic control in cancer cells that can serve to promote key oncogenic lipid signaling pathways that drive cancer pathogenicity.

Human Carboxylesterase 2 Reverses Obesity-Induced Diacylglycerol Accumulation and Glucose Intolerance

Summary Serine hydrolases are a large family of multifunctional enzymes known to influence obesity. Here, we performed activity-based protein profiling to assess the functional level of serine hydrolases in liver biopsies from lean and obese humans in order to gain mechanistic insight into the pathophysiology of metabolic disease. We identified reduced hepatic activity of carboxylesterase 2 (CES2) and arylacetamide deacetylase (AADAC) in human obesity. In primary human hepatocytes, CES2 knockdown impaired glucose storage and lipid oxidation. In mice, obesity reduced CES2, whereas adenoviral delivery of human CES2 reversed hepatic steatosis, improved glucose tolerance, and decreased inflammation. Lipidomic analysis identified a network of CES2-regulated lipids altered in human and mouse obesity. CES2 possesses triglyceride and diacylglycerol lipase activities and displayed an inverse correlation with HOMA-IR and hepatic diacylglycerol concentrations in humans. Thus, decreased CES2 is a conserved feature of obesity and plays a causative role in the pathogenesis of obesity-related metabolic disturbances.

Metabolic reprogramming ensures cancer cell survival despite oncogenic signaling blockade

There is limited knowledge about the metabolic reprogramming induced by cancer therapies and how this contributes to therapeutic resistance. Here we show that although inhibition of PI3K-AKT-mTOR signaling markedly decreased glycolysis and restrained tumor growth, these signaling and metabolic restrictions triggered autophagy, which supplied the metabolites required for the maintenance of mitochondrial respiration and redox homeostasis. Specifically, we found that survival of cancer cells was critically dependent on phospholipase A2 (PLA2) to mobilize lysophospholipids and free fatty acids to sustain fatty acid oxidation and oxidative phosphorylation. Consistent with this, we observed significantly increased lipid droplets, with subsequent mobilization to mitochondria. These changes were abrogated in cells deficient for the essential autophagy gene ATG5 Accordingly, inhibition of PLA2 significantly decreased lipid droplets, decreased oxidative phosphorylation, and increased apoptosis. Together, these results describe how treatment-induced autophagy provides nutrients for cancer cell survival and identifies novel cotreatment strategies to override this survival advantage.

Tumor cell-adipocyte gap junctions activate lipolysis and are essential for breast tumorigenesis

During tumorigenesis, a heterotypic interface exists between cancer and stromal cells that can both support and repress tumor growth. In the breast, studies have demonstrated a pro-tumorigenic role for adipocytes. However, the molecular mechanisms by which breast cancer cells coopt adipocytes remain elusive. Studying breast tumors and normal adjacent tissue (NAT) from several patient cohorts and mouse models, we show that lipolysis and lipolytic signaling are activated in NAT. We investigate the tumor-adipocyte interface and find that functional gap junctions form between breast cancer cells and adipocytes. As a result, cAMP, a critical lipolysis-inducing signaling molecule, is transferred from breast cancer cells to adipocytes and activates lipolysis in a gap junction-dependent manner; a fundamentally new mechanism of lipolysis activation in adipocytes. We find that gap junction formation depends upon connexin 31 (Cx31), and that Cx31 is essential for breast tumor growth and activation of lipolysis in vivo. Thus, direct tumor cell-adipocyte interaction is critical for tumorigenesis and may serve as a new therapeutic target in breast cancer. One sentence summary Gap junctions between breast cancer cells and adipocytes transfer cAMP and activate lipolysis in the breast tumor microenvironment.

Ablation of PM20D1 reveals N-acyl amino acid control of metabolism and nociception

Significance Bioactive lipids control a wide variety of physiologic processes. We have recently identified a branch of bioactive lipid signaling mediated by N-acyl amino acids (NAAs) and the circulating enzyme peptidase M20 domain-containing 1 (PM20D1). Here we generate and characterize mice globally deficient in PM20D1. These PM20D1-KO mice have bidirectional changes in NAA levels in blood and tissues and exhibit a variety of metabolic and nociceptive phenotypes. Our findings elucidate the endogenous physiologic functions for NAA signaling in vivo and suggest PM20D1 inhibitors might be useful for the treatment of pain. N-acyl amino acids (NAAs) are a structurally diverse class of bioactive signaling lipids whose endogenous functions have largely remained uncharacterized. To clarify the physiologic roles of NAAs, we generated mice deficient in the circulating enzyme peptidase M20 domain-containing 1 (PM20D1). Global PM20D1-KO mice have dramatically reduced NAA hydrolase/synthase activities in tissues and blood with concomitant bidirectional dysregulation of endogenous NAAs. Compared with control animals, PM20D1-KO mice exhibit a variety of metabolic and pain phenotypes, including insulin resistance, altered body temperature in cold, and antinociceptive behaviors. Guided by these phenotypes, we identify N-oleoyl-glutamine (C18:1-Gln) as a key PM20D1-regulated NAA. In addition to its mitochondrial uncoupling bioactivity, C18:1-Gln also antagonizes certain members of the transient receptor potential (TRP) calcium channels including TRPV1. Direct administration of C18:1-Gln to mice is sufficient to recapitulate a subset of phenotypes observed in PM20D1-KO animals. These data demonstrate that PM20D1 is a dominant enzymatic regulator of NAA levels in vivo and elucidate physiologic functions for NAA signaling in metabolism and nociception.