Abstract
Abstract Epithelial Ovarian Cancer (EOC) remains the leading cause of death in women with gynecologic malignancies, due to late diagnosis and early relapse associated with development of chemoresistance. We recently reported alterations of the choline-metabolite magnetic resonance spectral (MRS) profile in EOC cells, characterized by an increase content of phosphocholine (PCho). A multidisciplinary approach revealed that one of the more relevant changes was a significant increase of Choline Kinase (ChoK) activity (consistent with an increased protein and alpha-isoform mRNA expression) in cancer cells as compared to the normal counterpart. ChoK catalyzes the phosphorylation of choline to yield PCho as the first step in the biosynthesis of phosphatidylcholine, required for mammalian cell structural stability and proliferation. ChoK has been extensively related to cell proliferation being at the cross-roads of signalling pathways related to mitogenesis and survival and a prognostic role for ChoK in some cancer types has been described. Aim of the study is the evaluation of the biological relevance of ChoK expression and activity to define its possible role as a non-invasively detectable EOC biomarker and druggable target. We specifically silenced ChoK-alpha expression by transient RNA interference in two different EOC cell lines and evaluated the biological effects. Following ChoK-alpha silencing we observed a 70% reduction of mRNA and protein expression with a similar reduction in PCho accumulation as assessed by HMRS analysis. The ChoK-alpha silencing was accompanied by 20% inhibition of cell growth and similar percentage of cells blocked in the G1-phase of cell cycle. By transcriptome analysis we found CyclinA, related to regulation of cell cycle progression, and cytokines genes (IL-6 and IL-8) related to inflammation and EOC aggressiveness among the most relevant co-repressed genes, whereas among the most up-regulated genes we found Acyl-CoA synthetase and Osteoprotegerin. These observations suggest ChoK-alpha involvement in cell proliferation and survival. Evaluation of the biological effects of long-term Chok-alpha silencing by lentiviral transduction, together with concurrent inhibition of relevant survival signaling pathway (PI3K/AKT) or other enzymes involved in PCho metabolism (PC-PLC) is currently ongoing. To evaluate its possible role as prognostic biomarker, ChoK-alpha mRNA and protein expression is currently being analyzed on well characterized retrospective EOC case materials. The assessment of biological and prognostic relevance of choline metabolites might significantly contribute in the identification of new non-invasive diagnostic modalities and in the development of new targeted therapeutic approaches. (Partially supported by AIRC) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4076. doi:10.1158/1538-7445.AM2011-4076
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