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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.
Abstract:
The pharmacological activation of the cannabinoid receptor type 2, CB2, has been shown to elicit anti-tumoral mechanisms in different cancer types. However, little is known about its endogenous role in tumor pathophysiology, and different studies have attributed pro-tumorigenic properties to this receptor. In a previous work, we showed that CB2 expression is a poor prognostic factor in colon cancer patients. Here we report that activation of CB2 with low doses of specific agonists induce cell proliferation and favor the acquisition of aggressive molecular features in colon cancer cells. We show that sub-micromolar concentrations of CB2-specific agonists, JWH-133 and HU-308, promote an increase in cell proliferation rate through the activation of AKT/PKB pathway in colon cancer in vitro and in vivo. AKT activation promotes GSK3β inhibition and thus, a more aggressive cell phenotype with the subsequent elevation of SNAIL levels, E-cadherin degradation and β-catenin delocalization from cell membrane. Taken together, our data show that CB2 activation with sub-micromolar doses of agonists, which could be more similar to endogenous levels of cannabinoids, promote colon cancer progression, implicating that CB2 could have a pro-tumorigenic endogenous role in colon cancer.
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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