Abstract
Elucidation of molecular mechanisms underlying the aberrant phosphatidylcholine cycle in cancer cells plays in favor of the use of metabolic imaging in oncology and opens the way for designing new targeted therapies. The anomalous choline metabolic profile detected in cancer by magnetic resonance spectroscopy and spectroscopic imaging provides molecular signatures of tumor progression and response to therapy. The increased level of intracellular phosphocholine (PCho) typically detected in cancer cells is mainly attributed to upregulation of choline kinase, responsible for choline phosphorylation in the biosynthetic Kennedy pathway, but can also be partly produced by activation of phosphatidylcholine-specific phospholipase C (PC-PLC). This hydrolytic enzyme, known for implications in bacterial infection and in plant survival to hostile environmental conditions, is reported to be activated in mitogen- and oncogene-induced phosphatidylcholine cycles in mammalian cells, with effects on cell signaling, cell cycle regulation, and cell proliferation. Recent investigations showed that PC-PLC activation could account for 20–50% of the intracellular PCho production in ovarian and breast cancer cells of different subtypes. Enzyme activation was associated with PC-PLC protein overexpression and subcellular redistribution in these cancer cells compared with non-tumoral counterparts. Moreover, PC-PLC coimmunoprecipitated with the human epidermal growth factor receptor-2 (HER2) and EGFR in HER2-overexpressing breast and ovarian cancer cells, while pharmacological PC-PLC inhibition resulted into long-lasting HER2 downregulation, retarded receptor re-expression on plasma membrane and antiproliferative effects. This body of evidence points to PC-PLC as a potential target for newly designed therapies, whose effects can be preclinically and clinically monitored by metabolic imaging methods.
Highlights
Activation of Phosphatidylcholinespecific Phospholipase c in Breast and Ovarian cancer: impact on Mrs-Detected choline Metabolic Profile and Perspectives for targeted therapy
phosphatidylcholine-specific phospholipase C (PC-PLC) coimmunoprecipitated with the human epidermal growth factor receptor-2 (HER2) and EGFR in HER2-overexpressing breast and ovarian cancer cells, while pharmacological PC-PLC inhibition resulted into long-lasting HER2 downregulation, retarded receptor re-expression on plasma membrane and antiproliferative effects
Recent evidence shows protein overexpression and enzymatic activation of PC-PLC in breast cancer (BC) and epithelial ovarian cancer (EOC) cells compared with nontumoral counterparts
Summary
Phosphatidylcholine-specific phospholipase C (EC 3.1.4.3, here abbreviated as PC-PLC) is responsible for hydrolysis of this glycerophospholipid into phosphocholine (PCho) and 1,2-diacylglycerols (DAG). In another cell line (OVCAR3), the mean activity rate of ChoK was instead fourfold higher than that of PC-PLC Overall, these data showed that the contribution of PC-PLC to the PCho production could vary, according to the cell line, between 20% and 50%, in substantial agreement with the effects of D609 or si-RNA ChoK silencing on the PCho levels measured in different EOC cells [Figure 1C; [27, 56]]. Enzymatic assays in our laboratory [34] showed threefold to sixfold higher PC-PLC activity rates (ranging between 12 ± 2 and 22 ± 4 nmol/mg protein × h) in these BC cells versus the fibrocystic MCF-10 cell line (Figure 2A) Overall, these data suggest that the contribution of PC-PLC to the intracellular PCho production varied in these BC cells between 20% and 50%, as reported above for EOC cell lines. Reduced tumor growth and decrease in HER2 and Ki67 immunostaining were detected in SKOV3.ip xenografts upon in vivo treatment with D609, pointing to the interest of further evaluating the potential role of PC-PLC as a therapy target in preclinical HER2overexpressing EOC models
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