Activation of Phosphatidylcholine-Specific Phospholipase C in Breast and Ovarian Cancer: Impact on MRS-Detected Choline Metabolic Profile and Perspectives for Targeted Therapy

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.

Screening the active compounds of Phellodendri Amurensis cortex for treating prostate cancer by high-throughput chinmedomics

“…Choline metabolism is closely related to the occurrence and development of cancers5253. PC plays an important role in maintaining the physiological activity of cell membranes, thus it was a potential target in cancer diagnosis5455. Glycerophospholipid metabolism disorders are an important cancer marker: LysoPC, LysoPC(18:0) and sphingosine 1-phosphate are the signalling molecules of glycerophospholipid metabolism and the abnormal expression of these metabolite biomarkers indicates a disordered glycerophospholipid metabolism.…”

Functional link between plasma membrane spatiotemporal dynamics, cancer biology, and dietary membrane-altering agents

“…Likewise, a relative increase in lipid levels such as phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), phosphatidic acid (PA), and triglycerides (TG) as well as an increase in saturated fatty acid content has also been observed in a variety of tumor types [195–199]. In addition, increased expression of lipogenic enzymes, such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN), lipid-modifying enzymes such as phosphoinositide 3-kinase (PI3K), phospholipase C (PLC) and phospholipase D (PLD) and ATP citrate lyase (ACLY), which collectively promote cholesterol biosynthesis, represent a phenotypic alteration often observed in different cancer types and frequently predict a poor prognosis in cancer patients [199–204]. Furthermore, state-of-the-art analytical and imaging tools, such as electrospray ionization, matrix-assisted laser desorption/ionization, tandem mass spectrometry (MS/MS), and Raman scattering microscopy, have provided valuable lipidomic data that describe alterations in cellular lipid phenotype and fatty acid composition as well as specific spatial cellular distribution in cancer-related conditions [23, 196, 205–208].…”

Key Players in Choline Metabolic Reprograming in Triple-Negative Breast Cancer

“…Among these, phosphatidylinositol 4-phosphate 5-kinase Igamma (PIPKIγ) is overexpressed in TNBC cells, in which the loss of this enzyme impairs PI3K/Akt activation ( 28 ). Furthermore, two major enzymes involved in the agonist-induced phosphatidylcholine (PtdCho) cycle, such as choline kinase (ChoK) and PtdCho-specific phospholipase C (PC-PLC), are overexpressed and activated in various BC subtypes, including TNBC cells, with the implications on expression and oncogenic function of EGF receptors’ family members ( 29 – 33 ).…”

“…These PtdCho metabolites are produced through three major catabolic pathways, respectively, mediated by specific phospholipases of type C (PC-PLC) and D (PLD), which act at the two distinct phosphodiester bonds of the PtdCho headgroup, and by phospholipases of type A2 and A1 (PLA2 and PLA1), which act in the deacylation reaction cascade (Figure 2 ). PCho accumulation either produced by ChoK in the first reaction of the three-step Kennedy biosynthetic pathway or by PLC-mediated PtdCho catabolism is associated with tumor growth and progression ( 9 , 33 – 36 ).…”