Anandamide-Modulated Changes in Metabolism, Glycosylation Profile and Migration of Metastatic Melanoma Cells

Sobiepanek, Anna; Milner-Krawczyk, Małgorzata; Musolf, Paulina; Starecki, Tomasz; Kobiela, Tomasz

doi:10.3390/cancers14061419

Cited by 6 publications

(4 citation statements)

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“…We could also rule out the possibility that anandamide was simply toxic to the cells, as we saw no increase in 7-AAD positive cells ( Figure 1A ). This was an important control experiment, as others have reported significant cell death with similar concentrations in keratinocytes [10 μM, ( 43 )], melanoma cells [13.5 μM, ( 44 ); >5 μM, ( 45 )], sebocytes [>10 μM, ( 46 )], and murine DCs [>5 μM, ( 47 )].…”

Section: Discussionmentioning

confidence: 99%

Anandamide modulation of monocyte-derived Langerhans cells: implications for immune homeostasis and skin inflammation

Pénzes,

Horváth,

Molnár

et al. 2024

Front. Immunol.

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IntroductionThe endocannabinoid system (ECS), named after the chemical compounds found in the cannabis plant, is a regulatory network of neurotransmitters, receptors, and enzymes that plays crucial roles in skin health and disease. Endogenous ligands of the ECS, called endocannabinoids, have proven to be important regulators of immune responses. One of the most prevalent endocannabinoids, arachidonoylethanolamide (also known as anandamide), is known for its anti-inflammatory effects. Langerhans cells (LCs) are the sole antigen-presenting cells present in the human epidermis. They serve as the first line of defense against pathogens and are essential for the skin’s specific immune responses and play a critical role in maintaining tissue homeostasis; however, little is known about the effect of endocannabinoids on these cells. Our research aimed to provide the connection between monocyte-derived Langerhans cells (moLCs) and the ECS, shedding light on their collaborative roles in immune homeostasis and inflammation.MethodsHuman monocytes were differentiated into moLCs using established protocols. Anandamide was applied during the differentiation process to test its effect on the viability, marker expression, and cytokine production of the cells, as well as in short term treatments for intracellular calcium measurement. TLR ligands applied after the differentiation protocol were used to activate moLCs. The impact of anandamide on the functionality of moLCs was further assessed using differential gene expression analysis of bulk RNA-Seq data, moLC-T cell cocultures, while ELISpot was employed to determine polarization of T cells activated in the aforementioned cocultures.ResultsAnandamide did not significantly affect the viability of moLCs up to 10 µM. When applied during the differentiation process it had only a negligible effect on CD207 expression, the prototypic marker of LCs; however, there was an observed reduction in CD1a expression by moLCs. Anandamide had no significant effects on the maturation status of moLCs, nor did it affect the maturation induced by TLR3 and TLR7/8 agonists. MoLCs differentiated in the presence of anandamide did however show decreased production of CXCL8, IL-6, IL-10 and IL-12 cytokines induced by TLR3 and TLR7/8 activation. Anandamide-treated moLCs showed an increased capability to activate naïve T cells; however, not to the level seen with combined TLR agonism. RNA sequencing analysis of moLCs differentiated with anandamide showed modest changes compared to control cells but did reveal an inhibitory effect on oxidative phosphorylation specifically in activated moLCs. Anandamide also promoted the polarization of naïve T cells towards a Th1 phenotype.DiscussionOur results show that anandamide has nuanced effects on the differentiation, maturation, cytokine secretion, metabolism and function of activated moLCs. Among these changes the decrease in CD1a expression on moLCs holds promise to selectively dampen inflammation induced by CD1a restricted T cells, which have been implicated as drivers of inflammation in common inflammatory skin conditions such as psoriasis, atopic dermatitis and contact dermatitis.

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Section: Discussionmentioning

confidence: 99%

Anandamide modulation of monocyte-derived Langerhans cells: implications for immune homeostasis and skin inflammation

Pénzes,

Horváth,

Molnár

et al. 2024

Front. Immunol.

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“…ROS (Reactive Oxygen Species) assay. The methodology was adapted from previous work [27]. Media from 24 h cultures grown in 96-well plates were discarded, and the cells were gently washed with PBS.…”

Section: Metabolic Activity Tests-mtt Crystal Violet and Ros Assaysmentioning

confidence: 99%

Exploring Extracellular Vesicles of Probiotic Yeast as Carriers of Biologically Active Molecules Transferred to Human Intestinal Cells

Mierzejewska,

Kowalska,

Marlicka

et al. 2023

IJMS

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Extracellular vesicles (EVs) are nanoparticles containing various bioactive cargos—e.g., proteins, RNAs, and lipids—that are released into the environment by all cell types. They are involved in, amongst other functions, intercellular communication. This article presents studies on EVs produced by the probiotic yeast Saccharomyces boulardii CNCM I-745. The size distribution and concentration of EVs in the liquid culture of yeast were estimated. Moreover, the vesicles of S. boulardii were tested for their cytotoxicity against three model human intestinal cell lines. This study did not show any significant negative effect of yeast EVs on these cells under tested conditions. In addition, EVs of S. boulardii were verified for their ability to internalize in vitro with human cells and transfer their cargo. The yeast vesicles were loaded with doxorubicin, an anticancer agent, and added to the cellular cultures. Subsequently, microscopic observations revealed that these EVs transferred the compound to human intestinal cell lines. A cytotoxicity test confirmed the activity of the transferred doxorubicin. Detailed information about the proteins present in EVs might be important in terms of exploring yeast EVs as carriers of active molecules. Thus, proteomic analysis of the EV content was also conducted within the present study, and it allowed the identification of 541 proteins after matching them to the Saccharomyces Genome Database (SGD). Altogether, this study provides strong evidence that the EVs of the probiotic CNCM I-745 strain could be considered a drug delivery system.

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“…Moreover, evidence regarding cannabinoid ability to affect the Wnt pathway, thus altering the epithelial-mesenchymal transition and chemoresistance, has been shown in different tumor types and has been associated with a reduction of β-catenin target genes and mesenchymal markers [ 9 ]. Focusing on N-arachidonoyl-ethanolamine, anandamide (AEA), the cannabinoid used in this study, previous in vitro results demonstrated its role in the inhibition of breast tumor-induced angiogenesis [ 10 ] and the alteration of metabolism, glycosylation profile, and migration of metastatic melanoma cells [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

A zebrafish HCT116 xenograft model to predict anandamide outcomes on colorectal cancer

et al. 2022

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Colon cancer is one of the leading causes of death worldwide. In recent years, cannabinoids have been extensively studied for their potential anticancer effects and symptom management. Several in vitro studies reported anandamide’s (AEA) ability to block cancer cell proliferation and migration, but evidence from in vivo studies is still lacking. Thus, in this study, the effects of AEA exposure in zebrafish embryos transplanted with HCT116 cells were evaluated. Totally, 48 hpf xenografts were exposed to 10 nM AEA, 10 nM AM251, one of the cannabinoid 1 receptor (CB1) antagonist/inverse agonists, and to AEA + AM251, to verify the specific effect of AEA treatment. AEA efficacy was evaluated by confocal microscopy, which demonstrated that these xenografts presented a smaller tumor size, reduced tumor angiogenesis, and lacked micrometastasis formation. To gain deeper evidence into AEA action, microscopic observations were completed by molecular analyses. RNA seq performed on zebrafish transcriptome reported the downregulation of genes involved in cell proliferation, angiogenesis, and the immune system. Conversely, HCT116 cell transcripts resulted not affected by AEA treatment. In vitro HCT116 culture, in fact, confirmed that AEA exposure did not affect cell proliferation and viability, thus suggesting that the reduced tumor size mainly depends on direct effects on the fish rather than on the transplanted cancer cells. AEA reduced cell proliferation and tumor angiogenesis, as suggested by socs3 and pcnp mRNAs and Vegfc protein levels, and exerted anti-inflammatory activity, as indicated by the reduction of il-11a, mhc1uba, and csf3b mRNA. Of note, are the results obtained in groups exposed to AM251, which presence nullifies AEA’s beneficial effects. In conclusion, this study promotes the efficacy of AEA in personalized cancer therapy, as suggested by its ability to drive tumor growth and metastasis, and strongly supports the use of zebrafish xenograft as an emerging model platform for cancer studies.

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Anandamide-Modulated Changes in Metabolism, Glycosylation Profile and Migration of Metastatic Melanoma Cells

Cited by 6 publications

References 84 publications

Anandamide modulation of monocyte-derived Langerhans cells: implications for immune homeostasis and skin inflammation

Anandamide modulation of monocyte-derived Langerhans cells: implications for immune homeostasis and skin inflammation

Exploring Extracellular Vesicles of Probiotic Yeast as Carriers of Biologically Active Molecules Transferred to Human Intestinal Cells

A zebrafish HCT116 xenograft model to predict anandamide outcomes on colorectal cancer

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