title: Alterations of choline phospholipid metabolism in endometrial cancer are caused by choline kinase alpha overexpression and a hyperactivated deacylation pathway.
abstract: Metabolic rearrangements subsequent to malignant transformation are not well characterized in endometrial cancer. Identification of altered metabolites could facilitate imaging-guided diagnosis, treatment surveillance, and help to identify new therapeutic options. Here, we used high-resolution magic angle spinning magnetic resonance mass spectroscopy on endometrial cancer surgical specimens and normal endometrial tissue to investigate the key modulators that might explain metabolic changes, incorporating additional investigations using qRT-PCR, Western blotting, tissue microarrays (TMA), and uptake assays of [(3)H]-labeled choline. Lipid metabolism was severely dysregulated in endometrial cancer with various amino acids, inositols, nucleobases, and glutathione also altered. Among the most important lipid-related alterations were increased phosphocholine levels (increased 70% in endometrial cancer). Mechanistic investigations revealed that changes were not due to altered choline transporter expression, but rather due to increased expression of choline kinase α (CHKA) and an activated deacylation pathway, as indicated by upregulated expression of the catabolic enzymes LYPLA1, LYPLA2, and GPCPD1. We confirmed the significance of CHKA overexpression on a TMA, including a large series of endometrial hyperplasia, atypical hyperplasia, and adenocarcinoma tissues, supporting a role for CHKA in malignant transformation. Finally, we documented several-fold increases in the uptake of [(3)H]choline in endometrial cancer cell lines compared with normal endometrial stromal cells. Our results validate deregulated choline biochemistry as an important source of noninvasive imaging biomarkers for endometrial cancer.
authors.affiliation: Comprehensive Cancer Imaging Centre at Imperial College, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Trousil
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, United Kingdom. Department of Experimental Medicine, Imperial College London, London, United Kingdom.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Lee
authors.affiliation: Department of Experimental Medicine, Imperial College London, London, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Pinato
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
authors.forename: James K
authors.initials: JK
authors.lastname: Ellis
authors.affiliation: Department of Pathology, Imperial College NHS Trust, London, United Kingdom.
authors.forename: Roberto
authors.initials: R
authors.lastname: Dina
authors.affiliation: Comprehensive Cancer Imaging Centre at Imperial College, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Eric O
authors.initials: EO
authors.lastname: Aboagye
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
authors.forename: Hector C
authors.initials: HC
authors.lastname: Keun
authors.affiliation: Department of Experimental Medicine, Imperial College London, London, United Kingdom. r.sharma@imperial.ac.uk.
authors.forename: Rohini
authors.initials: R
authors.lastname: Sharma
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002794:Choline / Q000378:metabolism*; D002797:Choline Kinase / Q000096:biosynthesis* / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000201:enzymology / Q000378:metabolism*; D005260:Female; D006801:Humans; D006965:Hyperplasia / Q000378:metabolism; D050356:Lipid Metabolism; D008875:Middle Aged; D010740:Phospholipases / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism*; D010767:Phosphorylcholine / Q000378:metabolism; D015398:Signal Transduction; D013869:Thiolester Hydrolases / Q000378:metabolism
chemical_list: D010743:Phospholipids; D010767:Phosphorylcholine; C517212:CHKA protein, human; D002797:Choline Kinase; C573928:GPCPD1 protein, human; D010740:Phospholipases; C402226:LYPLA1 protein, human; C581317:LYPLA2 protein, human; D013869:Thiolester Hydrolases; D002794:Choline