Phosphatidylcholine-34:2 And-36:4 Have Tumor Suppressive Function For Gastric Cancer

Imaging mass spectrometry (IMS) is an emerging technique that enables us the quantitation and visualization of a number of biomolecules including phospholipids. Because antibodies against lipid molecules are hard to generate, IMS is a useful approach for lipid biology. Our colleagues and we used IMS apparatus named “iMScope™ (Shimadzu)” to detect the cancer specific phospholipids in liver, colorectal, oral, and breast cancer. Here, to identify possible anti-cancer drug candidate(s) for GC with no side effects, we performed an imaging mass spectrometry screening using a panel of non-neoplastic and neoplastic gastric tissue. Two species of phosphatidylcholine (PC), PC-36:4 and PC-34:2, were highly downregulated in GC. PC-36:4 and PC-34:2 suppressed the transformation of NIH3T3 cells driven by K-rasV12 and growth of 4 out of 8 GC cell lines, while the growth of non-transformed NIH3T3 was not affected by these lipids. Tumor growth of GC cells was also inhibited in nude mice on administration (i.v.) of these lipids without any side effects in vivo. Phosphorylation of Akt was downregulated by these lipids in some GC cell lines. In an immunohistochemical analysis, the expression of a PC-36:4 and PC-34:2 producing enzyme, LPCAT3, was diminished in GC tissue, and the low expression level of LPCAT3 was a predictor of poor survival of GC patients. Considering that PCs generally have no toxic effect for human, these data indicate the usefulness of PC-36:4 and PC-34:2 as potential anti-cancer drugs of GC. Stating the biochemical background of this observation, phospholipids are constituents of lipid bilayer and consist of a glycerol backbone, two esterified acyl chains, and a polar head group; phospholipids are classified into five subclass by the head group: phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI), or phosphatidylglycerol (PG). The Lands’ cycle produces the diversity of acyl chains’ compositions in phospholipids by phospholipase A2 and lysophospholipid acyltransferases. Recently, novel regulatory mechanisms of Akt activation via phospholipids were reported. For example, PS can bind Akt to induce conformational change, which facilitates the activation of Akt. On the other hand, a specific species of PC suppresses the interaction of Akt to phosphatidylinositol-3,4,5-trisphosphate to inhibit the downstream signaling. Because other specific phospholipids show the physiological functions in lipogenesis, fatty acid use, hepatic steatosis, and diabetes, the combination of the acyl chains are thought to define the functional properties of PCs. In these contexts, our data first disclosed that a specific PC plays a tumor suppressing role and possibly be a anti-cancer agent with minimal side-effect. Furthermore, our in vitro analysis was mechanistically rational in terms of the Akt-centered pathway of carcinogenesis. Citation Format: Nobuya Kurabe, Masako Suzuki, Yusuke Inoue, Tomoaki Kahyo, Moriya Iwaizumi, Hiroyuki Konno, Mitsutoshi Setou, Haruhiko Sugimura. Phosphatidylcholine-34:2 and -36:4 have tumor suppressive function for gastric cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 394A.