Activation of phosphatidylcholine cycle enzymes in human epithelial ovarian cancer cells

Egidio Iorio, Alessandro Ricci, Marina Bagnoli, Maria Elena Pisanu, Giancarlo Castellano, Massimo Di Vito, Elisa Venturini, Kristine Glunde, Zaver M. Bhujwalla, Delia Mezzanzanica, Silvana Canevari, Franca Podo

Research output: Contribution to journalArticle

Abstract

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 ChoKα (but not ChoKâ) 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 ChoKα 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 byosinthesis and degradation, respectively.

Original languageEnglish (US)
Pages (from-to)2126-2135
Number of pages10
JournalCancer Research
Volume70
Issue number5
DOIs
StatePublished - Mar 1 2010

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Iorio, E., Ricci, A., Bagnoli, M., Pisanu, M. E., Castellano, G., Di Vito, M., Venturini, E., Glunde, K., Bhujwalla, Z. M., Mezzanzanica, D., Canevari, S., & Podo, F. (2010). Activation of phosphatidylcholine cycle enzymes in human epithelial ovarian cancer cells. Cancer Research, 70(5), 2126-2135. https://doi.org/10.1158/0008-5472.CAN-09-3833