Adenosine induces apoptosis in the human gastric cancer cells via an intrinsic pathway relevant to activation of AMP-activated protein kinase

Saitoh, Masaru; Nagai, Kazuo; Nakagawa, Kazuhiko; Yamamura, Takehira; Yamamoto, Satoshi; Nishizaki, Tomoyuki

doi:10.1016/j.bcp.2004.01.020

Cited by 152 publications

(107 citation statements)

References 26 publications

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“…These antitumour effects might be counteracted to some extent by adenosine, produced after breakdown of ATP by ectonucleotidase, which is known to promote proliferation of tumour cells, as well as acting as an immunosuppressant [32][33][34][35][36]. However, adenosine has also been shown to have anti-tumour effects by inhibiting tumour growth via A 3 receptors [37][38][39] or by inhibiting apoptosis [40]. Further studies are needed to resolve these contradictory issues.…”

Section: Discussionmentioning

confidence: 99%

An in vivo model of melanoma: treatment with ATP

White

Knight

Butler

et al. 2009

Purinergic Signalling

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Athymic mice, injected with A375 human melanoma cells, were treated daily with intraperitoneal injections of adenosine 5′-triphosphate (ATP). The tumour volume and animal weight were measured over the course of the experiment and the final tumour nodule weight was measured at the end of the experiment. Tumour volume decreased by nearly 50% by 7 weeks in treated mice. Weight loss in untreated animals was prevented by ATP. Histological examination of the excised tumour nodules showed necrosis in the ATP-treated tumours only. The presence of P2Y 1 and P2X 7 receptors, previously proposed as extracellular targets for melanoma treatment with ATP, were demonstrated in the excised specimens by immunohistochemistry. This paper provides further support for the use of ATP as a treatment for melanoma.

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Section: Discussionmentioning

confidence: 99%

An in vivo model of melanoma: treatment with ATP

White

Knight

Butler

et al. 2009

Purinergic Signalling

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“…Although intact LKB1/AMPK signaling in normal tissues may protect against the development of cancer, in transformed cells, AMPK activation has been shown to be substantially cytotoxic to a variety of human cancer cell lines in vitro including lung, 30 prostate, 31,32 stomach, 33 liver, 34 breast 32,35 and glial. 32 In addition, 5-aminoimidazole-4-carboxamide-1-b-D-ribofuranoside, an activator of AMPK, reduced tumor growth in vivo in a rat C6 glioma allograft, 32 and in MDA-MB-231 human breast cancer xenografts.…”

Section: Ampk Activation In Cancer Cellsmentioning

confidence: 99%

AMP-activated protein kinase and human cancer: cancer metabolism revisited

Kuhajda

2008

Int J Obes

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AMP-activated protein kinase (AMPK) and its upstream kinase, LKB1, act to both monitor and restore cellular energy in response to energy depletion. Studied extensively in liver and skeletal muscle, AMPK is phosphorylated and activated by LKB1 in response to increasing AMP/ATP ratios, which occur in a variety of settings including hypoxia, nutrient starvation and redox imbalance. Interest in the roles of both AMPK and LKB1 in cancer has grown substantially, following the identification of LKB1 as the tumor suppressor gene mutated in the Peutz-Jegher familial cancer syndrome. Patients with the Peutz-Jegher syndrome harbor a single inactive LKB1 gene, and acquisition of a second inactivating lesion (loss of heterozygosity) leads to the development of the cancer in a variety of organs. Thus, the loss of AMPK activation is hypothesized to promote the development of malignancy. Conversely, pharmacological AMPK activation has recently been shown to be cytotoxic to many established human cancer cell lines in vitro and in human cancer xenograft and mouse cancer allografts. Previously, changes in cell metabolism that accompanied the malignant phenotype have largely been considered a consequence of cellular transformation. Now, AMPK and energy metabolism are linked to the development and maintenance of the malignant phenotype. These findings have led to renewed interest in AMPK and cancer cell metabolism in general as potential targets for cancer therapy.

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“…As a consequence of these metabolic shifts, adenosine may induce apoptosis of different malignant cells via upregulation of p53 (17) or AMP-activated protein kinase (AMPK; ref. 18) activities, translocation of apoptosis-inducing factor AMID from the cytosol into the nucleus (19), and other mitochondrial apoptotic pathways (15). Likewise, high concentrations of adenosine receptor agonists, antagonists, and other nucleoside analogues also trigger antiproliferative and cytotoxic effects on normal and leukemic cells via receptor-independent mechanisms (3,20,21), presumably acting as antimetabolites competing with natural nucleosides and inhibiting key enzymes of purine homeostasis.…”

Section: Introductionmentioning

confidence: 99%

Adenosine Inhibits Tumor Cell Invasion via Receptor-Independent Mechanisms

Virtanen

Kukkonen-Macchi

Vainio

et al. 2014

Molecular Cancer Research

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Extracellular adenosine mediates diverse anti-inflammatory, angiogenic, and other signaling effects via binding to adenosine receptors, and it also regulates cell proliferation and death via activation of the intrinsic signaling pathways. Given the emerging role of adenosine and other purines in tumor growth and metastasis, this study evaluated the effects of adenosine on the invasion of metastatic prostate and breast cancer cells. Treatment with low micromolar concentrations of adenosine, but not other nucleosides or adenosine receptor agonists, inhibited subsequent cell invasion and migration through Matrigel-and laminin-coated inserts. These inhibitory effects occurred via intrinsic receptor-independent mechanisms, despite the abundant expression of A2B adenosine receptors (ADORA2B). Extracellular nucleotides and adenosine were shown to be rapidly metabolized on tumor cell surfaces via sequential ecto-5 0 -nucleotidase (CD73/NT5E) and adenosine deaminase reactions with subsequent cellular uptake of nucleoside metabolites and their intracellular interconversion into ADP/ATP. This was accompanied by concurrent inhibition of AMP-activated protein kinase and other signaling pathways. No differences in the proliferation rates, cytoskeleton assembly, expression of major adhesion molecules [integrin1b (ITGB1), CD44, focal adhesion kinase], and secretion of matrix metalloproteinases were detected between the control and treated cells, thus excluding the contribution of these components of invasion cascade to the inhibitory effects of adenosine. These data provide a novel insight into the ability of adenosine to dampen immune responses and prevent tumor invasion via two different, adenosine receptor-dependent and -independent mechanisms.Implications: This study suggests that the combined targeting of adenosine receptors and modulation of intracellular purine levels can affect tumor growth and metastasis phenotypes.

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Adenosine induces apoptosis in the human gastric cancer cells via an intrinsic pathway relevant to activation of AMP-activated protein kinase

Cited by 152 publications

References 26 publications

An in vivo model of melanoma: treatment with ATP

An in vivo model of melanoma: treatment with ATP

AMP-activated protein kinase and human cancer: cancer metabolism revisited

Adenosine Inhibits Tumor Cell Invasion via Receptor-Independent Mechanisms

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