Activation of Phosphatidylcholine Cycle Enzymes in Human Epithelial Ovarian Cancer Cells

• Published in: Cancer research (Chicago, Ill.) Ill.), 2010-03, Vol.70 (5), p.2126-2135
• Main Authors: IORIO, Egidio, RICCI, Alessandro, CANEVARI, Silvana, PODO, Franca, BAGNOLI, Marina, PISANU, Maria Elena, CASTELLANO, Giancarlo, DI VITO, Massimo, VENTURINI, Elisa, GLUNDE, Kristine, BHUJWALLA, Zaver M, MEZZANZANICA, Delia
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Biological and medical sciences; Choline Kinase - biosynthesis; Choline Kinase - genetics; Choline Kinase - metabolism; Enzyme Activation; Epithelial Cells - pathology; Female; Female genital diseases; Gynecology. Andrology. Obstetrics; Humans; Medical sciences; Membrane Transport Proteins - biosynthesis; Membrane Transport Proteins - genetics; Membrane Transport Proteins - metabolism; Ovarian Neoplasms - enzymology; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Pharmacology. Drug treatments; Phosphatidylcholines - biosynthesis; Phospholipase D - metabolism; Phosphoric Diester Hydrolases - metabolism; Tumors; Type C Phospholipases - metabolism
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-09-3833

Altered phosphatidylcholine (PC) metabolism in epithelial ovarian cancer (EOC) could provide choline-based imaging approaches as powerful tools to improve diagnosis and identify new therapeutic targets. The increase in the major choline-containing metabolite phosphocholine (PCho) in EOC compared with normal and nontumoral immortalized counterparts (EONT) may derive from (a) enhanced choline transport and choline kinase (ChoK)-mediated phosphorylation, (b) increased PC-specific phospholipase C (PC-plc) activity, and (c) increased intracellular choline production by PC deacylation plus glycerophosphocholine-phosphodiesterase (GPC-pd) or by phospholipase D (pld)-mediated PC catabolism followed by choline phosphorylation. Biochemical, protein, and mRNA expression analyses showed that the most relevant changes in EOC cells were (a) 12-fold to 25-fold ChoK activation, consistent with higher protein content and increased ChoKalpha (but not ChoKbeta) mRNA expression levels; and (b) 5-fold to 17-fold PC-plc activation, consistent with higher, previously reported, protein expression. PC-plc inhibition by tricyclodecan-9-yl-potassium xanthate (D609) in OVCAR3 and SKOV3 cancer cells induced a 30% to 40% reduction of PCho content and blocked cell proliferation. More limited and variable sources of PCho could derive, in some EOC cells, from 2-fold to 4-fold activation of pld or GPC-pd. Phospholipase A2 activity and isoform expression levels were lower or unchanged in EOC compared with EONT cells. Increased ChoKalpha mRNA, as well as ChoK and PC-plc protein expression, were also detected in surgical specimens isolated from patients with EOC. Overall, we showed that the elevated PCho pool detected in EOC cells primarily resulted from upregulation/activation of ChoK and PC-plc involved in PC biosynthesis and degradation, respectively.