Adenosine A2b receptor promotes progression of human oral cancer

Kasama, Hiroki; Sakamoto, Yosuke; Kasamatsu, Atsushi; Okamoto, Atsushi; Koyama, Tomoyoshi; Minakawa, Yasuyuki; Ogawara, Katsunori; Yokoe, Hidetaka; Shiiba, Masashi; Tanzawa, Hideki; Uzawa, Katsuhiro

doi:10.1186/s12885-015-1577-2

Cited by 71 publications

(69 citation statements)

References 40 publications

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“…In fact, A2BR has been suggested to negatively regulate cell adhesion by modulating the localization of Rap1 protein (41). Others have suggested that A2BR controls carcinoma proliferation via HIF1a activation, indicating that A2BR may have several mechanisms to regulate tumor progression (42,43). Both RNAi silencing and pharmacologic blockade of A2BR inhibited filopodia formation and invasive activity of breast cancer cells and correspondingly reduced tumor outgrowth in the lungs (17).…”

Section: Discussionmentioning

confidence: 99%

Adenosine 2B Receptor Expression on Cancer Cells Promotes Metastasis

et al. 2016

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Adenosine plays an important role in inflammation and tumor development, progression, and responses to therapy. We show that an adenosine 2B receptor inhibitor (A2BRi) decreases both experimental and spontaneous metastasis and combines with chemotherapy or immune checkpoint inhibitors in mouse models of melanoma and triple-negative breast cancer (TNBC) metastasis. Decreased metastasis upon A2BR inhibition is independent of host A2BR and lymphocytes and myeloid cells. Knockdown of A2BR on mouse and human cancer cells reduces their metastasis in vivo and decreases their viability and colony-forming ability, while transiently delaying cell-cycle arrest in vitro. The prometastatic activity of adenosine is partly tumor A2BR dependent and independent of host A2BR expression. In humans, TNBC cell lines express higher A2BR than luminal and Her2 þ breast cancer cell lines, and high expression of A2BR is associated with worse prognosis in TNBC. Collectively, high A2BR on mouse and human tumors promotes cancer metastasis and is an ideal candidate for therapeutic intervention. Cancer Res; 76(15); 4372-82. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 99%

Adenosine 2B Receptor Expression on Cancer Cells Promotes Metastasis

et al. 2016

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“…In addition, the A 2B AR has been implicated in cell proliferation and angiogenesis, accounting for its apparent role in the pathogenesis of a number of solid tumors (Li et al, 2005;Ryzhov et al, 2008;Ma et al, 2010;Cekic et al, 2012;Iannone et al, 2013;Wei et al, 2013). The involvement of the A 2B AR in the proliferation of human oral squamous cell carcinoma-derived cells was confirmed with small hairpin RNA (Kasama et al, 2015). Furthermore, previous studies have demonstrated the inhibitory effects of an A 2B AR inverse agonist on the cell proliferation of human colon carcinomas (Ma et al, 2010) and prostate cancer cells (Wei et al, 2013); however, these studies were performed in the presence of endogenous adenosine and thus were unable to differentiate between the influence of agonist tone and any potential ligand-independent receptor activity.…”

Section: Discussionmentioning

confidence: 91%

Ligand-Independent Adenosine A2B Receptor Constitutive Activity as a Promoter of Prostate Cancer Cell Proliferation

Vecchio

Tan

Gregory

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Aberrant ligand-independent G protein-coupled receptor constitutive activity has been implicated in the pathophysiology of a number of cancers. The adenosine A 2B receptor (A 2B AR) is dynamically upregulated under pathologic conditions associated with a hypoxic microenvironment, including solid tumors. This, in turn, may amplify ligand-independent A 2B AR signal transduction. The contribution of A 2B AR constitutive activity to disease progression is currently unknown yet of fundamental importance, as the preferred therapeutic modality for drugs designed to reduce A 2B AR constitutive activity would be inverse agonism as opposed to neutral antagonism. The current study investigated A 2B AR constitutive activity in a heterologous expression system and a native 22Rv1 human prostate cancer cell line exposed to hypoxic conditions (2% O 2 ). (4-chlorophenyl)piperazide-1-sulfonyl)phenyl)-1-propylxanthine), mediated a concentration-dependent decrease in baseline cAMP levels in both cellular systems. Proliferation of multiple prostate cancer cell lines was also attenuated in the presence of PSB-603. Importantly, both the decrease in baseline cAMP accumulation and the reduction of proliferation were not influenced by the addition of adenosine deaminase, demonstrating that these effects are not dependent on stimulation of A 2B ARs by the endogenous agonist adenosine. Our study is the first to reveal that wild-type human A 2B ARs have high constitutive activity in both model and native cells. Furthermore, our findings demonstrate that this ligand-independent A 2B AR constitutive activity is sufficient to promote prostate cancer cell proliferation in vitro. More broadly, A 2B AR constitutive activity may have wider, currently unappreciated implications in pathologic conditions associated with a hypoxic microenvironment.

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“…[107,108] Other studies indicate that A 2B adenosine receptor is highly expressed also in oral squamous carcinoma cell lines, as well as in human oral carcinoma tissues, where its expression is correlated with those of HIF-1. [109] Studies by Gessi et al [110] demonstrate that in colon cancer cells, although at the mRNA levels A 2B receptor is more expressed than A 1 , A 2A and A 3 , the density of A 3 receptors is the highest among the adenosine receptor subtypes. Later, other studies have demonstrated that the adenosine A 2B receptor is up-regulated in colorectal carcinoma tissues and colon cancer cell lines compared with normal colorectal mucosa under hypoxic conditions.…”

Section: A 2b Receptor and Tumor Stromamentioning

confidence: 98%

“…[113] Moreover, stimulation of A 2B receptor with a non-selective adenosine analog NECA induces apoptosis in ovarian cancer cells. [114] Nonetheless,while a number of studies demonstrate that stimulation of A 2B adenosine receptor in some cancer cell types promotes proliferation, whereby knockdown or pharmacological inhibition of this receptor reduces tumor cell growth and promotes apoptosis, [107][108][109][110][111] opposite results have been also described. [112,113] The discrepancy might likely depend on the cancer cell types, the expression levels of this receptor on tumor cells and the selectivity and/or concentrations of pharmacological tools used in the experimental settings.…”

Section: A 2b Receptor and Tumor Stromamentioning

confidence: 99%

Role of adenosine in tumor progression: focus on A2B receptor as potential therapeutic target

Sissi¹,

Morello²

2017

JCMT

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Adenosine receptors are a family of G-coupled receptors which mediate the antiinflammatory and immune-suppressive effects of adenosine in a damaged tissue. A large number of evidence indicate that the accumulation of adenosine under hypoxic conditions favors tumor progression, helping cancer cells to evade immune responses. Tumor cells and/ or lymphoid and myeloid cells can express the adenosine-generating enzyme CD73 and/or A 2A receptor, which in turn strongly suppresses an effective T-cell-mediated response, while promotes the activity of suppressive cells such as Treg and myeloid-derived suppressor cells. CD73 inhibitors and A 2A antagonists, either as single agents, or in combination with immune-checkpoints inhibitors such as anti PD-1 monoclonal antibodies, are currently in Phase I clinical trial in cancer patients. Recent studies show that A 2B receptor plays an important role in mediating the pro-tumor effects of adenosine, since its selective blockade can inhibit tumor growth in some murine tumor models. Targeting A 2B receptor reduces immunosuppression induced by myeloid cells and inhibits the stromal cells activity within the tumor microenvironment, limiting tumor angiogenesis and metastatic processes. Here, the authors review the current data on involvement of A 2B receptor in regulating tumor progression and discuss the development of A 2B receptor inhibitors as potential therapeutic agents in cancer treatment. Key words:CD73/A 2 adenosine receptors axis, A 2B adenosine receptor, tumor immunity, tumor metastasis, tumor angiogenesis, cancer treatment ABSTRACTArticle history:

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Adenosine A2b receptor promotes progression of human oral cancer

Cited by 71 publications

References 40 publications

Adenosine 2B Receptor Expression on Cancer Cells Promotes Metastasis

Adenosine 2B Receptor Expression on Cancer Cells Promotes Metastasis

Ligand-Independent Adenosine A2B Receptor Constitutive Activity as a Promoter of Prostate Cancer Cell Proliferation

Role of adenosine in tumor progression: focus on A2B receptor as potential therapeutic target

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