Dataset Information

Lipid Metabolism and Lipid Droplets in Pancreatic Cancer and Stellate Cells.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second deadliest cancer by 2030, and the overall 5-year survival rate is currently less than 7%. Cancer cells frequently exhibit reprogramming of their metabolic activity. It is increasingly recognized that aberrant de novo lipid synthesis and reprogrammed lipid metabolism are both associated with the development and progression of various cancers, including pancreatic cancer. In this review, the current knowledge about lipid metabolism and lipid droplets in pancreatic cancer is discussed. In the first part, molecular mechanisms of lipid metabolism and roles of enzymes involved in lipid metabolism which are relevant for pancreatic cancer research are presented. Further, preclinical studies and clinical trials with drugs/inhibitors targeting cancer metabolic systems in cancer are summarized. An increase of our knowledge in lipid metabolism in pancreatic cancer cells and in tumor stroma is important for developing novel strategies of future individualized therapies of pancreatic cancer.

SUBMITTER: Sunami Y

PROVIDER: S-EPMC5789353 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Lipid Metabolism and Lipid Droplets in Pancreatic Cancer and Stellate Cells.

Sunami Yoshiaki Y Rebelo Artur A Kleeff Jörg J

Cancers 20171223 1

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second deadliest cancer by 2030, and the overall 5-year survival rate is currently less than 7%. Cancer cells frequently exhibit reprogramming of their metabolic activity. It is increasingly recognized that aberrant de novo lipid synthesis and reprogrammed lipid metabolism are both associated with the development and progression of various cancers, including pancreatic cancer. In this review, the current knowledge about lipid met ...[more]

PMID: 29295482

Similar Datasets

Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) is the most lethal malignancy: it has a 5-year survival rate of less than 9%. Although surgical resection is an effective treatment for PDAC, only a small number of patients can have their tumors surgically removed. Thus, an urgent need to find new therapeutic targets for PDAC exists. Understanding the molecular mechanism of PDAC development is essential for the treatment of this malignancy. This research aimed to study the mechanisms of pancreatic stellate cells (PSCs), which regulate branched-chain amino acid (BCAA) metabolism in PDAC.MethodsDifferentially expressed proteins were detected via nanoliquid chromatography coupled to mass spectrometry (nano-LC-MS/MS). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment methods were used to find the valine-leucine-isoleucine (BCAA) degradation pathway. The levels of BCAAs in the sera and tissues of patients with PDAC were measured by using nuclear magnetic resonance (NMR). The functions of BCAA concentrations and the effects of activated pancreatic stellate cells (aPSCs) were also evaluated by performing Cell Counting Kit-8, colony formation, and wound healing assays.ResultsA total of 1,519 proteins with significantly differential expression were discovered in PDAC and adjacent tissues by using nano-LC-MS/MS. KEGG pathway enrichment analysis identified the BCAA degradation pathway. The content of BCAA in PDAC clinical samples was up-regulated. However, the addition of different concentrations of BCAA to PDAC cell culture medium failed to promote the proliferation and migration of PDAC cells. Given that analysis based on The Cancer Genome Atlas database showed that the number of aPSCs gradually increased with the progression of PDAC, the effects of aPSCs on PDAC cells were explored. After coculture with aPSCs, PDAC cell proliferation showed a significant increase, and the proteins involved in the BCAA degradation pathway in PDAC cells had also changed.ConclusionsaPSCs could regulate BCAA metabolism to enhance the progression of PDAC, indicating that the regulation of BCAA metabolism may serve as a new therapeutic direction for PDAC.

Project description:ObjectivesPolyunsaturated fatty acids (PUFAs) are structural components of membrane phospholipids and precursors of oxygenated lipid mediators with diverse functions, including the control of cell growth, inflammation and tumourigenesis. However, the molecular pathways that control the availability of PUFAs for lipid mediator production are not well understood. Here, we investigated the crosstalk of three pathways in the provision of PUFAs for lipid mediator production: (i) secreted group X phospholipase A2 (GX sPLA2) and (ii) cytosolic group IVA PLA2 (cPLA2α), both mobilizing PUFAs from membrane phospholipids, and (iii) adipose triglyceride lipase (ATGL), which mediates the degradation of triacylglycerols (TAGs) stored in cytosolic lipid droplets (LDs).MethodsWe combined lipidomic and functional analyses in cancer cell line models to dissect the trafficking of PUFAs between membrane phospholipids and LDs and determine the role of these pathways in lipid mediator production, cancer cell proliferation and tumour growth in vivo.ResultsWe demonstrate that lipid mediator production strongly depends on TAG turnover. GX sPLA2 directs ω-3 and ω-6 PUFAs from membrane phospholipids into TAG stores, whereas ATGL is required for their entry into lipid mediator biosynthetic pathways. ATGL controls the release of PUFAs from LD stores and their conversion into cyclooxygenase- and lipoxygenase-derived lipid mediators under conditions of nutrient sufficiency and during serum starvation. In starving cells, ATGL also promotes the incorporation of LD-derived PUFAs into phospholipids, representing substrates for cPLA2α. Furthermore, we demonstrate that the built-up of TAG stores by acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) is required for the production of mitogenic lipid signals that promote cancer cell proliferation and tumour growth.ConclusionThis study shifts the paradigm of PLA2-driven lipid mediator signalling and identifies LDs as central lipid mediator production hubs. Targeting DGAT1-mediated LD biogenesis is a promising strategy to restrict lipid mediator production and tumour growth.

Dataset Information

Lipid Metabolism and Lipid Droplets in Pancreatic Cancer and Stellate Cells.

Publications

Lipid Metabolism and Lipid Droplets in Pancreatic Cancer and Stellate Cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets