Protective effect of phosphatidylcholine on lysophosphatidylcholine‐induced cellular senescence in cholangiocyte

• Published in: Journal of hepato-biliary-pancreatic sciences 2019-12, Vol.26 (12), p.568-577
• Main Authors: Ohigashi, Toshikazu, Kanno, Keishi, Sugiyama, Akiko, Nguyen, Phuong Thao, Kishikawa, Nobusuke, Otani, Yuichiro, Kobayashi, Tomoki, Matsuo, Hiroaki, Tazuma, Susumu
• Format: Article
• Language: English
• Subjects: Bile Ducts - cytology; Bile Ducts - pathology; Cell Line; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Proliferation - physiology; Cellular Senescence - drug effects; Cellular Senescence - physiology; Cholangiocarcinoma; Cytotoxicity; Epithelial Cells - drug effects; Epithelial Cells - pathology; Epithelial Cells - physiology; Epithelial to mesenchymal transition; Humans; Lysophosphatidylcholine; Lysophosphatidylcholines - adverse effects; Lysophosphatidylcholines - pharmacology; Oxidative Stress - drug effects; Phosphatidylcholine; Phosphatidylcholines - pharmacology; Protective Agents - pharmacology; Reactive oxygen species; Reactive Oxygen Species - metabolism; Senescence; Senescence‐associated secretory phenotype
• ISSN: 1868-6974; 1868-6982
• DOI: 10.1002/jhbp.684

Background Pancreaticobiliary maljunction and intrahepatic gallstones are at a high risk for biliary malignancy. Lysophosphatidylcholine (LPC) is increased in the bile of these patients, and we have previously reported that LPC‐induced cytotoxicity causes senescence‐associated secretory phenotype (SASP) in cholangiocytes. We aimed to determine the protective effect of phosphatidylcholine (PC) on LPC‐induced cholangiocyte cytotoxicity. Methods MMNK‐1, a human immortalized cholangiocyte cell line was treated with LPC with or without PC. To assess the biological effects of SASP components on cholangiocarcinoma, HuH28 and HuCCT1 (human cholangiocarcinoma cell lines) were cultured in the conditioned media where MMNK‐1 cells treated with LPC. Results The presence of PC reduced reactive oxygen species generation and oxidative DNA damage in MMNK‐1 treated with LPC. Moreover, SA‐β‐gal activity was markedly downregulated by PC. The secretion of SASP components, including interleukin (IL)‐8, IL‐6, and C‐C motif chemokine ligand 2 was also substantially reduced in the presence of PC. Cellular proliferation and migration were enhanced in HuCCT1 and HuH28 cells when cultured in the conditioned media, and these observations were suppressed by simultaneous addition of PC. Conclusion PC protects cholangiocytes against LPC‐induced cytotoxicity and cellular senescence, suggesting its potential as a target for inhibiting LPC‐related carcinogenesis and its promotion. Highlight Pancreaticobiliary maljunction with intrahepatic gallstones is a high‐risk factor for biliary malignancy. The bile in this condition has increased amounts of lysophosphatidylcholine (LPC), which induces cytotoxicity causing the senescence‐associated secretory phenotype of cholangiocytes. Ohigashi and colleagues established that phosphatidylcholine protects cholangiocytes against LPC‐induced cytotoxicity and cellular senescence, and inhibits LPC‐related carcinogenesis.