Adenosine and adenosine receptors in the immunopathogenesis and treatment of cancer

Kazemi, Mohammad Hossein; Mohseni, Sahar Raoofi; Hojjat‐Farsangi, Mohammad; Anvari, Enayat; Ghalamfarsa, Ghasem; Mohammadi, Hamed; Jadidi‐Niaragh, Farhad

doi:10.1002/jcp.25873

Cited by 118 publications

(94 citation statements)

References 277 publications

(317 reference statements)

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“…Because this receptor recruits cAMP as a secondary messenger (Kazemi et al, ) we used CGS 21680 agonist to evaluate A2aR functionality by measuring cAMP in MIN6 cells. The EC50 value for this agonist has been calculated 2.4 µM.…”

Section: Resultsmentioning

confidence: 99%

A2a adenosine receptor agonist improves endoplasmic reticulum stress in MIN6 cell line through protein kinase A/ protein kinase B/ Cyclic adenosine monophosphate response element‐binding protein/ and Growth Arrest And DNA‐Damage‐Inducible 34/ eukaryotic Initiation Factor 2α pathways

Arasi

Shahrestanaki

Aghaei

2018

Journal Cellular Physiology

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Endoplasmic reticulum (ER) stress is one of the main molecular events underlying pancreatic beta cell (PBC) failure, apoptosis, and a decrease in insulin secretion. Recent studies have highlighted the fundamental role of A2a adenosine receptor (A2aR) in potentiation of insulin secretion and proliferation of PBCs. However, possible protective effects of A2aR signaling against ER stress have not been elucidated yet. Thus, in the present study, we aimed to investigate the effects of A2aR activation in MIN6 beta cells undergoing tunicamycin (TM)‐mediated ER stress. A2aR expression and activity were evaluated using real‐time polymerase chain reaction and measurement of the cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), phospho‐protein kinase B or Akt (p‐Akt)/Akt, and phospho‐Cyclic adenosine monophosphate response element‐binding protein/CREB levels in response to a specific agonist (CGS 21680). Survival and proliferation in TM and CGS 21680 cotreated cells were evaluated using 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT), annexin V–fluorescein isothiocyanate (FITC)/propidium iodide staining, colony formation, and 5‐bromo‐2′‐deoxyuridine (Brdu) assays. In addition, the effects of A2aR stimulation on insulin secretion were evaluated using the enzyme‐linked immunosorbent assay. B‐cell lymphoma 2 (Bcl‐2), phospho‐eukaryotic Initiation Factor 2α (p‐eIF2α)/eIF2α, growth arrest and DNA‐damage‐inducible 34 (GADD34), X‐box binding protein 1 (XBP‐1), spliced X‐box binding protein 1 (XBP‐1s), immunoglobulin heavy‐chain‐binding protein (BIP), and CCAAT‐enhancer‐binding protein homologous protein (CHOP) levels were evaluated using western blotting. Our results showed a decrease in A2aR expression and p‐Akt/Akt and p‐CREB/CREB levels in TM‐pretreated cells. We also mentioned that CGS 21680 effectively increased cell survival, proliferation, and insulin secretion in TM‐treated cells. The antiapoptotic effects were possibly mediated through Bcl‐2 upregulation. Our western blotting results indicated that A2aR effectively downregulated p‐eIF2α/eIF2α, XBP‐1, XBP‐1s, BIP, and CHOP levels, whereas GADD34 was upregulated. Altogether, the present study revealed that A2aR signaling through PKA/Akt/CREB mediators alleviated TM cytotoxicity effects in MIN6 beta cells. Thus, the stimulation of this receptor was seen as a new approach to control ER stress in the PBC cells.

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Section: Resultsmentioning

confidence: 99%

A2a adenosine receptor agonist improves endoplasmic reticulum stress in MIN6 cell line through protein kinase A/ protein kinase B/ Cyclic adenosine monophosphate response element‐binding protein/ and Growth Arrest And DNA‐Damage‐Inducible 34/ eukaryotic Initiation Factor 2α pathways

Arasi

Shahrestanaki

Aghaei

2018

Journal Cellular Physiology

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“…8 Accumulating evidences have revealed that A2A receptors respond to the adenosine stimulation and thus modulate multiple physiological and pathophysiological processes including memory formation, emotionstate alteration, inflammatory reaction, immune regulation, braininjury repair, and aging process. 9,10 Recent researches have revealed that elevated adenosine levels in extracellular tumor Abbreviations: BBB, blood-brain barrier; LDH, lactate dehydrogenase; SDF-1, Stromal cell-derived factor-1. microenvironment and the activation of A2A receptors contribute to the immune escape and promote the progression and metastasis of tumor cells.…”

Section: Introductionmentioning

confidence: 99%

Adenosine A2A receptor activation reduces brain metastasis via SDF‐1/CXCR4 axis and protecting blood‐brain barrier

Chen

Zhou

et al. 2020

Molecular Carcinogenesis

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Brain metastasis is a leading cause of death worldwide, but the mechanism involved remains unclear. Stromal cell‐derived factor‐1 (SDF‐1)/C‐X‐C motif chemokine receptor 4 (CXCR4) signaling has been reported to induce the directed metastasis of cancers, and adenosine A2A receptor activation suppresses the SDF‐1/CXCR4 interaction. However, whether A2A receptor activation implicates the SDF‐1/CXCR4 signaling pathway and thus modulates brain metastasis remains unclear. In this study, Western blot was performed to evaluate the protein levels. Cell invasion and migration assays were used to estimate the metastasis ability of PC‐9 cells. The viability of cells was demonstrated by lactate dehydrogenase and cell proliferation assays. And the findings in vitro were further identified in nude mice. Notably, adenosine A2A receptor activation inhibited the proliferation and viability of PC‐9 cells and thus suppressed the brain metastasis. A2A receptor stimulation protected the function of blood‐brain barrier (BBB). The suppression of brain metastasis and the protection of BBB by A2A receptor relied on SDF‐1/CXCR4 signaling, and treatment using A2A receptor agonist and CXCR4 antagonist protected the nude mice from malignancy metastasis in vivo. Adenosine A2A receptor activation suppressed the brain metastasis by implicating the SDF‐1/CXCR4 axis and protecting the BBB.

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“…We reasoned that our SLICE screening platform also could be used to identify gene deletions that allow T cells to escape various forms of suppression. We focused on adenosine, a key immunosuppressive factor in the tumor microenvironment (Allard et al, 2017;Beavis et al, 2017;Kazemi et al, 2018). We performed a genome-wide proliferation screen by stimulating T cells in the presence of an adenosine receptor 2 (A2A) agonist (CGS-21680) at a suppressive dose of 20µM ( Figure S6A) versus a vehicle control for four days (Jacobson and Gao, 2006).…”

Section: Slice Screen For Resistance To Immunosuppressive Adenosine Smentioning

confidence: 99%

Genome-wide CRISPR Screens in Primary Human T Cells Reveal Key Regulators of Immune Function

Shifrut

Carnevale

Tobin

et al. 2018

Preprint

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SUMMARYHuman T cells are central effectors of immunity and cancer immunotherapy. CRISPR-based functional studies in T cells could prioritize novel targets for drug development and improve the design of genetically reprogrammed cell-based therapies. However, large-scale CRISPR screens have been challenging in primary human cells. We developed a new method, sgRNA lentiviral infection with Cas9 protein electroporation (SLICE), to identify regulators of stimulation responses in primary human T cells. Genome-wide loss-of-function screens identified essential T cell receptor signaling components and genes that negatively tune proliferation following stimulation. Targeted ablation of individual candidate genes validated hits and identified perturbations that enhanced cancer cell killing. SLICE coupled with single-cell RNA-Seq revealed signature stimulation-response gene programs altered by key genetic perturbations. SLICE genome-wide screening was also adaptable to identify mediators of immunosuppression, revealing genes controlling response to adenosine signaling. The SLICE platform enables unbiased discovery and characterization of functional gene targets in primary cells.

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Adenosine and adenosine receptors in the immunopathogenesis and treatment of cancer

Cited by 118 publications

References 277 publications

A2a adenosine receptor agonist improves endoplasmic reticulum stress in MIN6 cell line through protein kinase A/ protein kinase B/ Cyclic adenosine monophosphate response element‐binding protein/ and Growth Arrest And DNA‐Damage‐Inducible 34/ eukaryotic Initiation Factor 2α pathways

A2a adenosine receptor agonist improves endoplasmic reticulum stress in MIN6 cell line through protein kinase A/ protein kinase B/ Cyclic adenosine monophosphate response element‐binding protein/ and Growth Arrest And DNA‐Damage‐Inducible 34/ eukaryotic Initiation Factor 2α pathways

Adenosine A2A receptor activation reduces brain metastasis via SDF‐1/CXCR4 axis and protecting blood‐brain barrier

Genome-wide CRISPR Screens in Primary Human T Cells Reveal Key Regulators of Immune Function

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