Cannabidiol inhibits lung cancer cell invasion and metastasis<i>via</i>intercellular adhesion molecule‐1

Ramer, Robert; Bublitz, Katharina; Freimuth, Nadine; Merkord, Jutta; Rohde, Helga; Haustein, Maria; Borchert, Philipp; Schmuhl, Ellen; Linnebacher, Michael; Hinz, Burkhard

doi:10.1096/fj.11-198184

Cited by 143 publications

(130 citation statements)

References 55 publications

(87 reference statements)

Supporting

Mentioning

120

Contrasting

Unclassified

Order By: Relevance

“…15,47 The inhibitory effect of cannabidiol, a non-CB1R, non-CB2R ligand, on tumor cell invasion has been attributed in some cases to the induction of TIMP1, and subsequent inhibition on MMPs. 48 However, other reports show down-regulation of both Mmp2 and Timp1 in human glioma cels by CB2R agonists. 47,49 Here, we found For personal use only.…”

Section: Discussionmentioning

confidence: 95%

Signaling through cannabinoid receptor 2 suppresses murine dendritic cell migration by inhibiting matrix metalloproteinase 9 expression

Adhikary¹,

Kocieda

Yen

et al. 2012

Blood

View full text Add to dashboard Cite

Administration of cannabinoid receptor 2 (CB2R) agonists in inflammatory and autoimmune disease and CNS injury models results in significant attenuation of clinical disease, and reduction of inflammatory mediators. Previous studies reported that CB2R signaling also reduces leukocyte migration. Migration of dendritic cells (DCs) to various sites is required for their activation and for the initiation of adaptive immune responses. Here, we report for the first time that CB2R signaling affects DC migration in vitro and in vivo, primarily through the inhibition of matrix metalloproteinase 9 (MMP-9) expression. Reduced MMP-9 production by DCs results in decreased migration to draining lymph nodes in vivo and in vitro in the matrigel migration assay. The effect on Mmp-9 expression is mediated through CB2R, resulting in reduction in cAMP levels, subsequent decrease in ERK activation, and reduced binding of c-Fos and c-Jun to Mmp-9 promoter activator protein 1 sites. We postulate that, by dampening production of MMP-9 and subsequent MMP-9-dependent DC migration, cannabinoids contribute to resolve acute inflammation and to reestablish homeostasis. Selective CB2R agonists might be valuable future therapeutic agents for the treatment of chronic inflammatory conditions by targeting activated immune cells, including DCs. IntroductionThe cannabinoid system consists of cannabinoid receptors and their ligands, including endocannabinoids, synthetic cannabinoid receptor agonists and antagonists, and phytocannabinoids. Several cannabinoid receptors have been described, that is, the classic cannabinoid receptor 1 (GPR) and GPR, the previously orphaned G-protein receptors GPR18 and GPR55, various ion channels, and intracellular peroxisome proliferator-activated receptor-␥ (reviewed in Pertwee et al 1 and Console-Bram 2 ). The 2 classic cannabinoid receptors, CB1R and CB2R, have different distribution and functions (reviewed in Kubajewska and Constantinescu 3 and Basu and Dittel 4 ). CB1R is abundantly expressed on CNS and peripheral neurons and involved in neural functions. In contrast, CB2R is mostly expressed on immune cells and involved in immunoregulation. Administration of CB2R-selective agonists in models of inflammatory and autoimmune diseases such as systemic sclerosis, experimental autoimmune uveoretinitis, inflammatory bowel diseases, and experimental autoimmune encephalomyelitis (EAE) resulted in attenuation of clinical disease (reviewed in Basu and Dittel 4 ). CB2R agonists also have been reported to have a beneficial effect in models of CNS injury such as cerebral infarction and spinal cord injury. [5][6][7][8] In addition to effects on clinical outcome, CB2R agonists reduced the levels of inflammatory mediators in various experimental models. [8][9][10] A possible mechanism for the anti-inflammatory effect of CB2R signaling is the direct action of CB2R agonists on immune cells. In vitro studies indicated that CB2R signaling inhibited the production of proinflammatory cytokines such as TNF␣, IL-6, IL-2, and IFN-␥ by ac...

show abstract

Section: Discussionmentioning

confidence: 95%

Signaling through cannabinoid receptor 2 suppresses murine dendritic cell migration by inhibiting matrix metalloproteinase 9 expression

Adhikary¹,

Kocieda

Yen

et al. 2012

Blood

View full text Add to dashboard Cite

show abstract

“…In a panel of tumor cell lines, cannabidiol even exhibited the most potent antiproliferative action as compared with a variety of other cannabinoids (3). Moreover, cannabidiol has been proven to exert anti-invasive properties on cervical (8), lung (9,10), and breast cancer cells (11) in vitro, an antimetastatic action on lung (8,10) and breast cancer cells (3), as well as tumor-regressive effects on solid tumors in vivo (3,9,10). Apart from its direct antitumorigenic action, cannabidiol has recently also been shown to relieve intractable and opioid-insensitive cancer pain (12) and to reduce severe adverse reactions associated with chemotherapy such as neurotoxic and nephrotoxic effects (13,14).…”

Section: Introductionmentioning

confidence: 99%

COX-2 and PPAR-γ Confer Cannabidiol-Induced Apoptosis of Human Lung Cancer Cells

Ramer

Heinemann

Merkord

et al. 2013

Molecular Cancer Therapeutics

Self Cite

171

150

View full text Add to dashboard Cite

The antitumorigenic mechanism of cannabidiol is still controversial. This study investigates the role of COX-2 and PPAR-g in cannabidiol's proapoptotic and tumor-regressive action. In lung cancer cell lines (A549, H460) and primary cells from a patient with lung cancer, cannabidiol elicited decreased viability associated with apoptosis. Apoptotic cell death by cannabidiol was suppressed by NS-398 (COX-2 inhibitor), GW9662 (PPAR-g antagonist), and siRNA targeting COX-2 and PPAR-g. Cannabidiol-induced apoptosis was paralleled by upregulation of COX-2 and PPAR-g mRNA and protein expression with a maximum induction of COX-2 mRNA after 8 hours and continuous increases of PPAR-g mRNA when compared with vehicle. In response to cannabidiol, tumor cell lines exhibited increased levels of COX-2-dependent prostaglandins (PG) among which PGD 2 and 15-deoxy-D 12,14 -PGJ 2 (15d-PGJ 2 ) caused a translocation of PPAR-g to the nucleus and induced a PPAR-g-dependent apoptotic cell death. Moreover, in A549-xenografted nude mice, cannabidiol caused upregulation of COX-2 and PPAR-g in tumor tissue and tumor regression that was reversible by GW9662. Together, our data show a novel proapoptotic mechanism of cannabidiol involving initial upregulation of COX-2 and PPAR-g and a subsequent nuclear translocation of PPAR-g by COX-2-dependent PGs. Mol Cancer Ther; 12(1); 69-82. Ó2012 AACR.

show abstract

“…Hence, the inhibitory effect of cannabinoids on lung cancer cell invasion and metastasis has been suggested to occur via up-regulation of ICAM-1, which then increases the tissue inhibitor of matrix metalloproteinases-1 [78]. ICAM-1 has also been suggested to mediate the differentiation properties of gastrin-releasing peptide on colon cancer cells by enhancing cell-matrix attachment [79].…”

Section: The Effect Of Leukotoxinmentioning

confidence: 99%

Role of LFA-1 and ICAM-1 in Cancer

Reina

Espel

2017

Preprint

View full text Add to dashboard Cite

The lymphocyte function-associated antigen-1 (LFA-1) (also CD11a/CD18 and αLβ2), is just one of many integrins in the human body, but its significance derives from its exclusive presence in leukocytes. In this review, we summarize the studies relating LFA-1 and its major ligand ICAM-1 (CD54) with cancer, through the function of lymphocytes and myeloid cells on tumor cells. We consider how LFA-1 mediates the interaction of leukocytes with tumors and the role of ICAM-1 in tumor dynamics, which can be independent of its interaction with LFA-1. A more detailed examination of LFA's role within B-cell chronic lymphocytic leukemia is made. Finally, we discuss the role of LFA-1-harboring exosomes in tumor growth and metastasis.Keywords: cancer metastasis; chronic lymphocytic leukemia; exosomes; tumor microenvironment LFA-1 is widely expressed in hematopoietic cells, mediating intercellular interactions within the immune system and between leukocytes and non-blood cells. Several intercellular adhesion molecules (ICAM), including ICAM-1 (CD54) are common ligands for LFA-1 [1] [2]. The strength of LFA-1 adhesion varies by adjusting the affinity (conformation), the level of LFA-1 clustering and the force applied by the ligand [3] [4] [5]. LFA-1 can adopt different conformations, from a folded low-affinity inactive one to an open active conformation. The stimulation of cells by receptors like the T-cell receptor or chemokine receptors changes the adhesive properties of LFA-1 in a process called "inside-out" signaling that may open the conformation of LFA-1 and expose its ligand-binding site [6]. In addition, it should be noted that the characteristics of the external ligand binding to LFA-1 initiates a signaling cascade in LFA-1 (named "outside-in" signaling), giving rise to various cellular changes [7]. As with other integrins, LFA-1 is not a mere adhesive contact between cells, but it also mediates signals that modulate the growth, differentiation and survival of the cell. LFA-1 participates in the cytotoxic immune response against tumorsThe T cell cytotoxic response against cancer cells starts when the T cell receptor recognizes a specific tumor antigen on the surface of the cancer cell; this is normally followed by delivery of toxic granules that kill the target cell. In the cytolytic response against virus-infected cells, the adhesion between the cytotoxic lymphocyte and the target cell is not strictly dependent on LFA-1, this however is necessary in the cytolytic response to immunogenic tumors [8] [9]. LFA-1 is an essential initiator of the immunological synapse that forms between the cytotoxic T or NK cell and the cancer cell, and mediates the firm adhesion to the target cell and the polarization of cytotoxic granules towards the target [7] [10] [11]. There is a positive correlation between the maturation state of NK cells, their cytotoxic potential and the activation level of LFA-1 [12].Tumor infiltrating lymphocytes need LFA-1 to adhere to target cells Cancer cells can escape from the immune response by chan...

show abstract

Cannabidiol inhibits lung cancer cell invasion and metastasisviaintercellular adhesion molecule‐1

Cited by 143 publications

References 55 publications

Signaling through cannabinoid receptor 2 suppresses murine dendritic cell migration by inhibiting matrix metalloproteinase 9 expression

Signaling through cannabinoid receptor 2 suppresses murine dendritic cell migration by inhibiting matrix metalloproteinase 9 expression

COX-2 and PPAR-γ Confer Cannabidiol-Induced Apoptosis of Human Lung Cancer Cells

Role of LFA-1 and ICAM-1 in Cancer

Contact Info

Product

Resources

About