Abstract
Cannabidiol (CBD) has been used to treat a variety of cancers and inflammatory conditions with controversial results. In previous work, we have shown that breast cancer MCF-7 cells, selected by their response to inflammatory IL-1β cytokine, acquire a malignant phenotype (6D cells) through an epithelial–mesenchymal transition (EMT). We evaluated CBD as a potential inhibitor of this transition and inducer of reversion to a non-invasive phenotype. It decreased 6D cell viability, downregulating expression of receptor CB1. The CBD blocked migration and progression of the IL-1β-induced signaling pathway IL-1β/IL-1RI/β-catenin, the driver of EMT. Cannabidiol reestablished the epithelial organization lost by dispersion of the cells and re-localized E-cadherin and β-catenin at the adherens junctions. It also prevented β-catenin nuclear translocation and decreased over-expression of genes for ∆Np63α, BIRC3, and ID1 proteins, induced by IL-1β for acquisition of malignant features. Cannabidiol inhibited the protein kinase B (AKT) activation, a crucial effector in the IL-1β/IL-1RI/β-catenin pathway, indicating that at this point there is crosstalk between IL-1β and CBD signaling which results in phenotype reversion. Our 6D cell system allowed step-by-step analysis of the phenotype transition and better understanding of mechanisms by which CBD blocks and reverts the effects of inflammatory IL-1β in the EMT.
Highlights
Inflammation is considered a critical component of cancer progression
Previous work by our group has shown that binding of the inflammatory cytokine IL-1β to its receptor IL-1RI, present in non-invasive MCF-7 breast cancer cells, triggered the initiation of epithelial–mesenchymal transition (EMT) by activation of the signaling pathway
As a first approach to this study, the effect of CBD on cell viability was evaluated in the 6D model of breast cancer cells
Summary
Inflammation is considered a critical component of cancer progression. The presence of inflammatory cytokines in the tumor microenvironment has been linked to an aggressive phenotype in cancer cells [1]. Previous work by our group has shown that binding of the inflammatory cytokine IL-1β to its receptor IL-1RI, present in non-invasive MCF-7 breast cancer cells, triggered the initiation of epithelial–mesenchymal transition (EMT) by activation of the signaling pathway. The β-catenin acted as a transcriptional coactivator, modulating the expression of genes and proteins downstream of the IL-1β-activated signaling pathway to complete the EMT and the acquisition of an aggressive phenotype of the so-called 6D cells. These data supported the proposal by us and other authors of a relationship between cancer development and an inflammatory microenvironment [6,7]
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