title: Prognostic impact of AMP-activated protein kinase expression in ovarian carcinoma: correlation of protein expression and GC/TOF-MS-based metabolomics.
abstract: AMP-activated protein kinase (AMPK) plays a central role in regulating energy metabolism in cells. AMPK activation results in down-regulation of anabolic pathways (e.g., fatty acid biosynthesis) and switches on catabolic processes such as glucose uptake, glycolysis or fatty acid oxidation. Recent studies in cell culture models have shown that the growth of tumor cell lines was inhibited by AMPK activation, but the expression of AMPK in human ovarian tumors has not been reported so far. In this study we investigated AMPK expression in a cohort of 70 ovarian carcinomas, 14 borderline tumors and 5 normal ovaries and linked the protein expression data to Gas chromatography/ time of flight mass spectrometry (GC/TOF-MS) based metabolomics. We observed a significantly higher expression in ovarian carcinomas compared to borderline tumors and normal ovaries (p=0.038). Decreased AMPK expression correlated significantly with higher tumor grade (p=0.009) and was of adverse prognosis in patients with advanced tumor stages (p=0.016) as well as in patients with serous ovarian carcinomas (p=0.037). GC/TOF-MS based metabolomics revealed a significantly higher concentration of glucose in AMPK-negative carcinomas (p=0.022) as well as overexpression of other metabolites from carbohydrate metabolism. Our results indicate a role for AMPK in progression of ovarian tumors and point towards a prognostic impact of AMPK expression for patient overall survival. Furthermore, our data suggest a deregulation of the AMPK-dependent energy metabolism in human ovarian carcinomas. In future clinical studies, activation of AMPK in ovarian carcinoma patients with advanced tumor stages might be an interesting therapeutic approach.
authors.affiliation: Institute of Pathology, Charité Universitaetsmedizin Berlin, Charitéplatz 1, D-10117 Berlin, Germany.
authors.forename: Ann-Christin
authors.initials: AC
authors.lastname: Buckendahl
authors.forename: Jan
authors.initials: J
authors.lastname: Budczies
authors.forename: Oliver
authors.initials: O
authors.lastname: Fiehn
authors.forename: Silvia
authors.initials: S
authors.lastname: Darb-Esfahani
authors.forename: Tobias
authors.initials: T
authors.lastname: Kind
authors.forename: Aurelia
authors.initials: A
authors.lastname: Noske
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
authors.forename: Jalid
authors.initials: J
authors.lastname: Sehouli
authors.forename: Elena
authors.initials: E
authors.lastname: Braicu
authors.forename: Manfred
authors.initials: M
authors.lastname: Dietel
authors.forename: Carsten
authors.initials: C
authors.lastname: Denkert
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018284:Cystadenocarcinoma, Serous / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007124:Immunoenzyme Techniques; D055432:Metabolomics; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D010053:Ovary / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D011494:Protein Kinases / Q000378:metabolism*; D015996:Survival Rate
chemical_list: D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases