Cannabinoids Transmogrify Cancer Metabolic Phenotype via Epigenetic Reprogramming and a Novel CBD Biased G Protein-Coupled Receptor Signaling Platform

Abstract

The concept of epigenetic reprogramming predicts long-term functional health effects. This reprogramming can be activated by exogenous or endogenous insults, leading to altered healthy and different disease states. The exogenous or endogenous changes that involve developing a roadmap of epigenetic networking, such as drug components on epigenetic imprinting and restoring epigenome patterns laid down during embryonic development, are paramount to establishing youthful cell type and health. This epigenetic landscape is considered one of the hallmarks of cancer. The initiation and progression of cancer are considered to involve epigenetic abnormalities and genetic alterations. Cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer development, including DNA methylation, histone modifications, nucleosome positioning, non-coding RNAs, and microRNA expression. Endocannabinoids are natural lipid molecules whose levels are regulated by specific biosynthetic and degradative enzymes. They bind to and activate two primary cannabinoid receptors, type 1 (CB1) and type 2 (CB2), and together with their metabolizing enzymes, form the endocannabinoid system. This review focuses on the role of cannabinoid receptors CB1 and CB2 signaling in activating numerous receptor tyrosine kinases and Toll-like receptors in the induction of epigenetic landscape alterations in cancer cells, which might transmogrify cancer metabolism and epigenetic reprogramming to a metastatic phenotype. Strategies applied from conception could represent an innovative epigenetic target for preventing and treating human cancer. Here, we describe novel cannabinoid-biased G protein-coupled receptor signaling platforms (GPCR), highlighting putative future perspectives in this field.

Functional Selectivity of Cannabinoid Type 1 G Protein-Coupled Receptor Agonists in Transactivating Glycosylated Receptors on Cancer Cells to Induce Epithelial–Mesenchymal Transition Metastatic Phenotype

“…This signaling platform potentiates MMP9 and Neu1 crosstalk on the cell surface, which is essential for activating TLR. Citation: Taken in part from Bunsick et al [ 52 ]. ( B ) Cells were allowed to adhere on 12 mm circular glass slides for 24 h at 37 °C in a humidified incubator.…”

“…It is not surprising that CB1 is in complex with Neu-1 as both have interactions with TLR4 [ 56 , 69 , 78 ], EGFR [ 11 , 54 ], Trks [ 6 , 79 ], and IR [ 7 , 8 , 9 ]. There is no debate that the increased expression of Neu-1 and MMP-9 has an impact on cancer progression through the modulation of inflammation, tumorigenesis, and insulin receptor signaling [ 52 , 68 , 80 ]. However, there is conflicting evidence on CB1 agonism and cancer metastasis.…”

“…However, there is conflicting evidence on CB1 agonism and cancer metastasis. Alternatively, some studies support the notion that CB1 agonism promotes cancer metastasis [ 52 , 81 ]. With findings that contradict one another, it may be challenging to elucidate the effectiveness by which endocannabinoids modulate cancer progression.…”

“…Nevertheless, given the importance of dimerization at this receptor subtype, mechanisms that involve the formation of CB1 dimers and oligomers are likely to be involved. For example, one oligomer-based signaling axis shown to mediate biased agonism at various GPCRs consists of the oligomerization of the GPCR with the NMBR receptor and a glycosylated receptor [ 52 , 86 , 87 , 88 ]. The dimerization of the GPCR with NMBR mediates crosstalk between the neuraminidase-1 (Neu-1) and matrix metalloproteinase-9 (MMP-9) enzymes, ultimately leading to the transactivation of glycosylated receptors and the biased activation of downstream signaling pathways.…”

“…This interesting imperative is underscored as emerging evidence has implicated the involvement of CB1 receptors in a biased GPCR signaling platform involving the dimerization of the GPCR with NMBR and subsequent crosstalk between the neuraminidase-1 and matrix metalloproteinase-9 enzymes, as reviewed elsewhere [ 9 , 52 ]. As depicted in Figure 7 , CB1 agonists may also induce epigenetic modifications by inducing the biased CB1-NMBR-Neu1-MMP9 signaling paradigm and indirectly stimulating the TLR through a process known as transactivation [ 8 , 52 , 86 , 89 ]. Subsequent activation of these glycosylated receptors facilitates the initiating and translocation of the NF-kB pathway into the nucleus, enabling the epigenetic reprogramming of gene expression [ 89 ].…”