CB2 cannabinoid receptor activation promotes colon cancer progression via AKT/GSK3β signaling pathway

Esther Martínez-Martínez1, Asunción Martín-Ruiz1, Paloma Martín2

  • 1Department of Medical Oncology, Hospital Universitario Puerta de Hierro-Majadahonda, E-28222 Madrid, Spain.

Oncotarget
|September 17, 2016
PubMed

Insights

Low doses of CB2 receptor agonists stimulate colon cancer cell proliferation and aggressive features. This suggests a pro-tumorigenic role for the CB2 receptor in colon cancer progression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Cannabinoid receptor type 2 (CB2) activation shows anti-tumoral effects in some cancers.
  • Its endogenous role in tumor pathophysiology and potential pro-tumorigenic effects are less understood.
  • CB2 expression is a known poor prognostic factor in colon cancer.

Purpose of the Study:

  • To investigate the endogenous role of CB2 receptor activation in colon cancer progression.
  • To determine the effect of low-dose CB2 agonists on colon cancer cell behavior and molecular features.
  • To elucidate the signaling pathways involved in CB2-mediated colon cancer cell changes.

Main Methods:

  • Utilized sub-micromolar concentrations of CB2-specific agonists (JWH-133, HU-308) in colon cancer cell models.
  • Assessed cell proliferation rates in vitro and in vivo.
  • Analyzed molecular changes including AKT/PKB pathway activation, GSK3β inhibition, SNAIL levels, E-cadherin, and β-catenin localization.

Main Results:

  • Low-dose CB2 activation significantly increased colon cancer cell proliferation.
  • This activation led to the acquisition of aggressive molecular features.
  • The AKT/PKB pathway was activated, promoting GSK3β inhibition, SNAIL elevation, E-cadherin degradation, and β-catenin delocalization.

Conclusions:

  • CB2 receptor activation at sub-micromolar concentrations promotes colon cancer progression.
  • These findings suggest a pro-tumorigenic endogenous role for CB2 in colon cancer.
  • Targeting CB2 signaling may offer new therapeutic strategies for colon cancer.

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