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5-aminosalicylic acid inhibits cell cycle progression in a phospholipase D dependent manner in colorectal cancer
  1. Bart Baan1,2,
  2. Ashwin A Dihal2,
  3. Eva Hoff2,
  4. Carina L Bos3,
  5. Philip W Voorneveld2,
  6. Pim J Koelink2,
  7. Manon E Wildenberg1,
  8. Vanesa Muncan1,
  9. Jarom Heijmans1,
  10. Hein W Verspaget2,
  11. Dick J Richel4,
  12. James C H Hardwick2,
  13. Daniel W Hommes2,
  14. Maikel P Peppelenbosch5,
  15. Gijs R van den Brink1,2,6
  1. 1Tytgat Institute for Liver & Intestinal Research, Academic Medical Center, Amsterdam, the Netherlands
  2. 2Department of Gastroenterology & Hepatology, Leiden University Medical Center, Leiden, the Netherlands
  3. 3Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands
  4. 4Department of Medical Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
  5. 5Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
  6. 6Department of Gastroenterology & Hepatology, Academic Medical Center, Amsterdam, the Netherlands
  1. Correspondence to Gijs R van den Brink, Department of Gastroenterology & Hepatology, C2, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; g.r.vandenbrink{at}amc.nl

Abstract

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.

  • 5-ASA
  • TOR serine-threonine Kinases
  • phospholipase D
  • colonic neoplasms
  • cell proliferation
  • chemoprevention
  • primary care
  • colorectal cancer screening
  • diet
  • psychosomatic medicine
  • cancer
  • molecular oncology
  • stem cells
  • small intestine cancer
  • pancreatic tumours
  • cellular immunology
  • Crohn's disease
  • dendritic cells
  • inflammatory bowel disease
  • oxidative metabolism
  • matrix metalloproteinase
  • immunology
  • IBD
  • immune response
  • cell biology
  • colonic adenomas
  • Hedgehog signalling
  • colon carcinogenesis
  • signal transduction

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Footnotes

  • The authors BB and AAD contributed equally.

  • Funding The research leading to these results was sponsored by an unrestricted grant from Ferring BV.

  • Competing interests None.

  • Ethics approval Medical Ethical Committee of University of Leiden.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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