Journal Article

5-aminosalicylic acid inhibits cell cycle progression in a phospholipase D dependent manner in colorectal cancer

Hommes, Daniel W, Bos, Carina L, Koelink, Pim J, Dihal, Ashwin A, Wildenberg, Manon E, Verspaget, Hein W, Muncan, Vanesa, Peppelenbosch, Maikel P, Hoff, Eva, van den Brink, Gijs R, Baan, Bart, Richel, Dick J, Hardwick, James C H, Voorneveld, Philip W, Heijmans, Jarom

2012

Overview

Background 5-aminosalicylic acid (5-ASA) may protect against the development of inflammation-associated colorectal cancer. In vitro data suggest that, in colorectal cancer cells, 5-ASA induces cell cycle arrest, but the molecular mechanism leading to this arrest remains to be determined. Aim To dissect the signal transduction events that lead to 5-ASA mediated inhibition of proliferation of colorectal cancer cells, focusing on mammalian target of rapamycin (mTOR), a regulator of cell cycle progression. Methods The influence of 5-ASA on mTOR signalling was examined in a panel of colorectal cancer cell lines. The effects of 5-ASA on the pathways that control mTOR activity were studied in detail in two different colorectal cancer cell lines, using western blot, siRNA, a phospholipase D (PLD) activity assay, proliferation assays and cell cycle analysis. The phosphorylation status of mTOR and its downstream target, ribosomal protein S6, was studied in colorectal cancers before and after topical 5-ASA treatment. Results Treatment of colorectal cancer with 5-ASA inhibited mTOR signalling in vitro and in vivo. 5-ASA had no effect on any of the pathways that regulate the activity of the tuberous sclerosis complex in colorectal cancer cells. Both proliferation and mTOR activity depended on PLD, an enzyme that generates phosphatidic acid (PA). 5-ASA treatment inhibited PLD activity and proliferation; these effects could be rescued with exogenous PA. Conclusion 5-ASA interferes with proliferation of colorectal cancer cells via inhibition of PLD-dependent generation of PA and loss of mTOR signalling.

• Publisher: BMJ Publishing Group Ltd and British Society of Gastroenterology,BMJ Publishing Group,BMJ Publishing Group LTD
• Subject: 5-ASA / Acids / Anti-Inflammatory Agents, Non-Steroidal - pharmacology / Anti-Inflammatory Agents, Non-Steroidal - therapeutic use / Biological and medical sciences / Biomarkers, Tumor - metabolism / Biopsy / Blotting, Western / Bones, joints and connective tissue. Antiinflammatory agents / cancer / cell biology / Cell cycle / Cell Cycle - drug effects / Cell growth / Cell Line, Tumor / cell proliferation / Cell Proliferation - drug effects / cellular immunology / chemoprevention / colon carcinogenesis / colonic adenomas / colonic neoplasms / Colorectal cancer / colorectal cancer screening / Colorectal Neoplasms - drug therapy / Colorectal Neoplasms - metabolism / Crohn's disease / dendritic cells / diet / Epidermal growth factor / Gastroenterology. Liver. Pancreas. Abdomen / Hedgehog signalling / Humans / IBD / immune response / immunology / Inflammatory bowel disease / Kinases / matrix metalloproteinase / Medical sciences / Mesalamine - pharmacology / Mesalamine - therapeutic use / molecular oncology / oxidative metabolism / pancreatic tumours / Pharmacology. Drug treatments / phospholipase D / Phospholipase D - metabolism / Phosphorylation / primary care / Proteins / psychosomatic medicine / Signal transduction / Signal Transduction - drug effects / small intestine cancer / stem cells / Stomach. Duodenum. Small intestine. Colon. Rectum. Anus / Studies / TOR serine-threonine Kinases / TOR Serine-Threonine Kinases - metabolism / Tumors