Silencing GDPD5, a novel anticancer target, increases glycerophosphocholine in human breast cancer cells

Introduction: Phosphocholine (PC) and total choline-containing compounds (tCho = glycerophosphocholine (GPC) + PC + free choline (Cho)) are elevated in human breast cancers, as demonstrated by numerous H magnetic resonance (MR) spectroscopy (MRS) studies [1, 2]. A switch from high GPC and low PC to low GPC and high PC characterizes the choline metabolite profile of breast [3] and ovarian [4] cancers. Choline phospholipid metabolism consists of a complex network of biosynthetic and catabolic pathways, with one or more enzymes acting per pathway [5]. Some of the enzymes in choline phospholipid metabolism may be potential targets for anticancer therapy. Previous studies on choline kinase downregulation by RNA interference (RNAi) reduced proliferation and increased differentiation in breast cancer cells [6]. Glycerophosphocholine phosphodiesterase (E.C. 3.1.4.2; GPC-PDE) is an enzyme in choline phospholipid metabolism that catalyzes the degradation of GPC to Cho and glycerol-3-phosphate. To our knowledge, the gene(s) for the GPC-PDE responsible for the low GPC concentration in breast cancer cells have not yet been identified. Glycerophosphodiester phosphodiesterase domain containing 5 (GDPD5) is a GPC-PDE that is rapidly inhibited by NaCl and urea in renal cells [7], and may be a candidate gene for GPC-PDE in breast cancer cells. In our current study, we inhibited for the first time GPC-PDE chemically by high concentrations of NaCl and urea, and downregulated GDPD5 by RNAi using short hairpin RNA (shRNA) against GDPD5.