Simultaneous Activation of Induced Heterodimerization between CXCR4 Chemokine Receptor and Cannabinoid Receptor 2 (CB2) Reveals a Mechanism for Regulation of Tumor Progression

Coke, Christopher J.; Scarlett, Kisha A.; Chetram, Mahandranauth A.; Jones, Kia J.; Sandifer, Brittney J.; Davis, Ahriea S.; Marcus, Adam I.; Hinton, Cimona V.

doi:10.1074/jbc.m115.712661

Cited by 80 publications

(90 citation statements)

References 90 publications

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“…Clinically, expression of CXCR4 protein in tumors is used to predict cancer aggressiveness, survival probability and metastasis-associated mortality [39, 40]. Few data about cannabinoids and CXCR4, indicate that CB2 modulates the CXCR4-induced transendothelial migration of T cells, altering multiple immune and inflammatory responses [41], and CB2 agonist specifically reduced CXCR4-mediated migration [13]. Regarding CD147, it has critical roles in intercellular communication involved in chronic inflammation, tumor metastasis and angiogenesis [42–44].…”

Section: Discussionmentioning

confidence: 99%

“…THC and CBD also show anti-inflammatory activities, by decreasing the release of pro-inflammatory cytokines (IFN-γ, IFN-β, IL-1 β, IL-6) and related transcription factors (such as NF-kB and STAT-3), in normal [12] and cancer cell lines, including MM [11]. Another important feature is that treatment with cannabinoids has been shown to reduce invasiveness of cancer cells as well as CXCR4-mediated migration of immune cells [13]. …”

Section: Introductionmentioning

confidence: 99%

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Cannabinoids synergize with carfilzomib, reducing multiple myeloma cells viability and migration

et al. 2016

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Several studies showed a potential anti-tumor role for cannabinoids, by modulating cell signaling pathways involved in cancer cell proliferation, chemo-resistance and migration. Cannabidiol (CBD) was previously noted in multiple myeloma (MM), both alone and in synergy with the proteasome inhibitor bortezomib, to induce cell death. In other type of human cancers, the combination of CBD with Δ9-tetrahydrocannabinol (THC) was found to act synergistically with other chemotherapeutic drugs suggesting their use in combination therapy. In the current study, we evaluated the effects of THC alone and in combination with CBD in MM cell lines. We found that CBD and THC, mainly in combination, were able to reduce cell viability by inducing autophagic-dependent necrosis. Moreover, we showed that the CBD-THC combination was able to reduce MM cells migration by down-regulating expression of the chemokine receptor CXCR4 and of the CD147 plasma membrane glycoprotein. Furthermore, since the immuno-proteasome is considered a new target in MM and also since carfilzomib (CFZ) is a new promising immuno-proteasome inhibitor that creates irreversible adducts with the β5i subunit of immuno-proteasome, we evaluated the effect of CBD and THC in regulating the expression of the β5i subunit and their effect in combination with CFZ. Herein, we also found that the CBD and THC combination is able to reduce expression of the β5i subunit as well as to act in synergy with CFZ to increase MM cell death and inhibits cell migration. In summary, these results proved that this combination exerts strong anti-myeloma activities.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cannabinoids synergize with carfilzomib, reducing multiple myeloma cells viability and migration

et al. 2016

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“…The simplest hypothesis being that B cell activation is associated with a down-regulation of the surface CB 2 receptor. Alternatively, it has been reported that CB 2 can form heterodimers with the CXCR4 chemokine receptor and has chemotactic properties that result in the selective homing of CB 2 + and CB 2 − B cells to different regions of lymphoid follicles (Basu et al 2013; Coke et al 2016). We addressed the potential linkage between B cell activation and CB 2 expression using two different approaches.…”

Section: Discussionmentioning

confidence: 99%

“…The presence of an activated phenotype on B cells is specifically associated with down-regulation of the surface CB 2 receptor, a feature identified in B cells recovered from human tonsils and also observed in vitro when naïve B cells were stimulated to acquire an activated phenotype. Given the capacity for cell surface CB 2 to form heterodimers with chemokine receptors and promote migration and homing and given the location of CB 2 + and CB 2 − B cells in different compartments within lymphoid follicles (Basu et al 2013; Coke et al 2016), it is possible that modulating surface CB 2 during B cell activation plays an important role in trafficking. The capacity for T cells, dendritic cells, and malignant B cells to respond to cannabinoids in a CB 2 -dependent manner has been well characterized (McKallip et al 2002; Roth et al 2015; Yuan et al 2002), yet these cells do not express CB 2 on the cell surface.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Cell Surface CB2 Receptor during Human B Cell Activation and Differentiation

Castaneda

Harui

Roth

2017

J Neuroimmune Pharmacol

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Cannabinoid receptor type 2 (CB2) is the primary receptor pathway mediating the immunologic consequences of cannabinoids. We recently reported that human peripheral blood B cells express CB2 on both the extracellular membrane and at intracellular sites, where-as monocytes and T cells only express intracellular CB2. To better understand the pattern of CB2 expression by human B cells, we examined CD20+ B cells from three tissue sources. Both surface and intracellular expression were present and uniform in cord blood B cells, where all cells exhibited a naïve mature phenotype (IgD+/CD38Dim). While naïve mature and quiescent memory B cells (IgD−/CD38−) from tonsils and peripheral blood exhibited a similar pattern, tonsillar activated B cells (IgD−/CD38+) expressed little to no surface CB2. We hypothesized that regulation of the surface CB2 receptor may occur during B cell activation. Consistent with this, a B cell lymphoma cell line known to exhibit an activated phenotype (SUDHL-4) was found to lack cell surface CB2 but express intracellular CB2. Furthermore, in vitro activation of human cord blood resulted in a down-regulation of surface CB2 on those B cells acquiring the activated phenotype but not on those retaining IgD expression. Using a CB2 expressing cell line (293T/CB2-GFP), confocal microscopy confirmed the presence of both cell surface expression and multifocal intracellular expression, the latter of which co-localized with endoplasmic reticulum but not with mitochondria, lysosomes, or nucleus. Our findings suggest a dynamic multi-compartment expression pattern for CB2 in B cells that is specifically modulated during the course of B cell activation.

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“…So far, it is unknown whether TSHR also constitutes functionally relevant heterodimers with other GPCRs, but it would be of enormous importance to clarify this question because heterodimerization could have dramatic consequences on TSHR functionalities as known from other GPCRs (156–160) and many different GPCRs are expressed in the same tissues as TSHR [e.g., searchable in Ref. (161)].…”

Section: Available Structural Informationmentioning

confidence: 99%

Structural–Functional Features of the Thyrotropin Receptor: A Class A G-Protein-Coupled Receptor at Work

et al. 2017

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The thyroid-stimulating hormone receptor (TSHR) is a member of the glycoprotein hormone receptors, a sub-group of class A G-protein-coupled receptors (GPCRs). TSHR and its endogenous ligand thyrotropin (TSH) are of essential importance for growth and function of the thyroid gland and proper function of the TSH/TSHR system is pivotal for production and release of thyroid hormones. This receptor is also important with respect to pathophysiology, such as autoimmune (including ophthalmopathy) or non-autoimmune thyroid dysfunctions and cancer development. Pharmacological interventions directly targeting the TSHR should provide benefits to disease treatment compared to currently available therapies of dysfunctions associated with the TSHR or the thyroid gland. Upon TSHR activation, the molecular events conveying conformational changes from the extra- to the intracellular side of the cell across the membrane comprise reception, conversion, and amplification of the signal. These steps are highly dependent on structural features of this receptor and its intermolecular interaction partners, e.g., TSH, antibodies, small molecules, G-proteins, or arrestin. For better understanding of signal transduction, pathogenic mechanisms such as autoantibody action and mutational modifications or for developing new pharmacological strategies, it is essential to combine available structural data with functional information to generate homology models of the entire receptor. Although so far these insights are fragmental, in the past few decades essential contributions have been made to investigate in-depth the involved determinants, such as by structure determination via X-ray crystallography. This review summarizes available knowledge (as of December 2016) concerning the TSHR protein structure, associated functional aspects, and based on these insights we suggest several receptor complex models. Moreover, distinct TSHR properties will be highlighted in comparison to other class A GPCRs to understand the molecular activation mechanisms of this receptor comprehensively. Finally, limitations of current knowledge and lack of information are discussed highlighting the need for intensified efforts toward TSHR structure elucidation.

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Simultaneous Activation of Induced Heterodimerization between CXCR4 Chemokine Receptor and Cannabinoid Receptor 2 (CB2) Reveals a Mechanism for Regulation of Tumor Progression

Cited by 80 publications

References 90 publications

Cannabinoids synergize with carfilzomib, reducing multiple myeloma cells viability and migration

Cannabinoids synergize with carfilzomib, reducing multiple myeloma cells viability and migration

Regulation of Cell Surface CB2 Receptor during Human B Cell Activation and Differentiation

Structural–Functional Features of the Thyrotropin Receptor: A Class A G-Protein-Coupled Receptor at Work

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