TNF-related apoptosis-inducing ligand cooperates with NSAIDs via activated Wnt signalling in (pre)malignant colon

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Published on: October 27, 2014

Dianne M Heijink1, Mathilde Jalving, Dorenda Oosterhuis

  • 1Department of Medical Oncology, University Medical Centre Groningen, University of Groningen, The Netherlands.

The Journal of Pathology
|December 21, 2010
PubMed

Insights

Non-steroidal anti-inflammatory drugs (NSAIDs) enhance TRAIL-receptor agonistic agents

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Colorectal cancer chemoprevention and treatment can involve TNF-related apoptosis-inducing ligand (TRAIL) receptor agonists and non-steroidal anti-inflammatory drugs (NSAIDs).
  • Investigating the synergistic effects of NSAIDs and TRAIL agonists in colorectal cancer is crucial for developing novel therapeutic strategies.
  • The Wnt signalling pathway plays a significant role in colon cancer development and may influence treatment response.

Purpose of the Study:

  • To determine if NSAIDs sensitize colon cancer and adenoma cell lines, as well as ex vivo human adenomas, to recombinant human (rh)TRAIL.
  • To examine the involvement of the Wnt signalling pathway in NSAID-mediated sensitization to rhTRAIL.
  • To assess the potential of combining TRAIL agonists and NSAIDs as a treatment for colorectal (pre)malignant tumours.

Main Methods:

  • Treatment of colon cancer cell lines, adenoma cell lines, ex vivo human adenomas, and normal colonic epithelium with aspirin or sulindac in combination with rhTRAIL.
  • Assessment of apoptosis levels, intracellular protein expression, and TRAIL receptor membrane expression.
  • Utilisation of colon cancer cells with a dominant-negative TCF-4 construct to analyse the role of Wnt pathway activation.

Main Results:

  • NSAIDs, particularly aspirin, significantly sensitized both rhTRAIL-sensitive and -resistant colon cancer cell lines to rhTRAIL (maximum enhancement ratio, 7.1).
  • Sulindac demonstrated the most effective sensitization of adenoma cell lines to rhTRAIL (maximum enhancement ratio, 2.5).
  • Combinational treatment enhanced caspase-8 activation, and NSAID-induced sensitization was dependent on TCF-4 activity, indicating Wnt pathway involvement.

Conclusions:

  • NSAID-induced sensitization to rhTRAIL in colon cancer cells is dependent on TCF-4 activity, highlighting the importance of the Wnt signalling pathway.
  • The combination of TRAIL-receptor agonistic agents and NSAIDs presents a promising therapeutic approach for colorectal tumours with active Wnt signalling.
  • This combination therapy warrants further investigation for the treatment of (pre)malignant colorectal conditions.

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