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Review
. 2021 Apr 1;22(7):3680.
doi: 10.3390/ijms22073680.

Molecular Mechanism of Cannabinoids in Cancer Progression

Cristina Pagano  1 , Giovanna Navarra  1 , Laura Coppola  1 , Maurizio Bifulco  1 , Chiara Laezza  2
Affiliations
Review

Molecular Mechanism of Cannabinoids in Cancer Progression

Cristina Pagano et al. Int J Mol Sci. .

Abstract

Cannabinoids are a family of heterogeneous compounds that mostly interact with receptors eliciting several physiological effects both in the central and peripheral nervous systems and in peripheral organs. They exert anticancer action by modulating signaling pathways involved in cancer progression; furthermore, the effects induced by their use depend on both the type of tumor and their action on the components of the endocannabinoid system. This review will explore the mechanism of action of the cannabinoids in signaling pathways involved in cancer proliferation, neovascularisation, migration, invasion, metastasis, and tumor angiogenesis.

Keywords: angiogenesis; cancer; cannabinoids; cell death; migration.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Main anticancer molecular pathways mediated by cannabinoids. Cannabinoids inhibit cell cycle progression (↓cyclin-CDK complexes, ↓cAMP, ↑ROS↓, PI3K/Akt), can induce apoptosis (ROS↑, caspase8-9↑, MAPK/ERK↓, PI3K/Akt↓) and autophagy (Ceramide↑, ER STRESS↑, mTORC1/2↓, LC3-II↑) by activation of cannabinoid receptors CB1 or CB2, but can be also induced by mechanisms independent of CB1 and CB2 receptors.
Figure 2
Figure 2
Schematic representation of the main mechanisms mediated by cannabinoids on angiogenesis, EMT, adhesion, invasion, and metastasis. Cannabinoids through the WNT/catenin pathway reduce the expression of genes implicated in EMT (snail1, twist, slug, and vimentin) and increase the expression of E-cadherin. Cannabinoids reduce angiogenesis and metastasis through release of extracellular vesicles containing miR-29b1 and inhibiting phosphorylation of AKT and expression of MMP2, MMP9, FAK, and VCAM1. Angiogenesis is inhibited by CB2 receptor binding CXCR4 receptor and by expression of TIMP1. Instead, AM251 inhibited adhesion and EMT, not through the CB receptor but via TGF-beta and P38 Map-kinase. Cannabinoids through GPR55 receptor decrease expression of Id-1 (helix-loop-helix transcription factor inhibitor of DNA binding 1) and consequentially of Sox 2 to inhibit angiogenesis and metastasis.
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