Intracellularly transported adenosine induces apoptosis in HuH-7 human hepatoma cells by downregulating c-FLIP expression causing caspase-3/-8 activation

Yang, Dongqin; Yaguchi, Takahiro; Yamamoto, Hideyuki; Nishizaki, Tomoyuki

doi:10.1016/j.bcp.2007.01.020

Cited by 52 publications

(53 citation statements)

References 32 publications

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“…Adenosine-induced Hepg2 cell apoptosis has been demonstrated in our previous studies (12,13) and by others (10,29). the typical morphological hallmarks of apoptosis include nuclear condensation, nuclear fragmentation and the formation of apoptotic bodies in the absence of an inflammatory reaction (35).…”

Section: Discussionmentioning

confidence: 56%

Involvement of endoplasmic reticulum stress in adenosine-induced human hepatoma HepG2 cell apoptosis

Ye²,

Huang³

et al. 2011

Oncol Rep

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Abstract. endoplasmic reticulum stress (ers)-mediated cell apoptosis has been implicated in the development of multiple diseases such as cancer, neurodegenerative diseases and ischemic reperfusion damage. previous studies have demonstrated the adenosine-induced apoptosis in several tumor cell lines. However, the role of ers in adenosine-induced human hepatoma Hepg2 cell apoptosis remains unclear. the present study was designed to determine whether ers is involved in adenosine-induced Hepg2 cell apoptosis. the Mtt assay was used to determine proliferation, and DApI staining of cell nuclei was performed to determine cell apoptosis. the translocation of cHop and caspase-3 was observed by immunofluorescence analysis, and the protein expression of CHOP, caspase-4 and caspase-3 was detected by Western blotting. the Mtt assay demonstrated that adenosine inhibited Hepg2 cell proliferation in a dose-dependent manner. DApI staining of cell nuclei and cell cycle analysis verified cell apoptosis. The immunofluorescence assay demonstrated that adenosine induced the translocation of cHop and of caspase-3 from the cytoplasm to the nucleus. Western blotting confirmed that cHop, caspase-4 and caspase-3 were up-regulated in Hepg2 cells after treatment with adenosine. However, JnK protein expression was not altered. These results show that ERS is involved in the adenosine-induced Hepg2 cell apoptosis.

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Section: Discussionmentioning

confidence: 56%

Involvement of endoplasmic reticulum stress in adenosine-induced human hepatoma HepG2 cell apoptosis

Ye²,

Huang³

et al. 2011

Oncol Rep

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“…Gastrointestinal epithelial cells are constantly renewed at short-term intervals. A decline in ADA activity and the ensuing increase in intracellular adenosine concentrations could also peel off the gastrointestinal epithelium by inducing apoptosis, in light of the fact that higher concentrations of adenosine induce apoptosis in a variety of cells [6,7,8,9]. When adenosine concentrations in organs with higher ADA activity are beyond control, as is the case with ADA-deficient disease, cells in those organs might more easily undergo apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…ADA deficiency should cause an increase in adenosine concentrations. Accumulating studies have shown that high concentrations of adenosine induce apoptosis in a variety of cancer cells [6,7,8,9]. Then, we hypothesized that high concentrations of adenosine in parallel with decreased ADA activity might be a factor for pathogenesis of gastrointestinal diseases such as gastric ulcer, i.e.…”

Section: Introductionmentioning

confidence: 99%

Caspase-4 Activation in Association with Decreased Adenosine Deaminase Activity May Be a Factor for Gastric Ulcer

et al. 2009

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Background/Aims: Adenosine deaminase (ADA)-deficient disease, a severe combined immunodeficiency, is most commonly associated with gastrointestinal disorders such as ulcer. The present study investigated the role of ADA in the pathogenesis of gastric ulcer. Methods: ADA activity was measured in a variety of organs and tissues from rats and in human gastric biopsy samples from patients who underwent gastrofiberscope. An MTT assay and TUNEL staining were carried out, and activity of caspase-3 and -4 was enzymatically measured in MKN45 human gastric cancer cells. In the Western blot analysis, caspase-4 activation was identified in gastric biopsy samples. Results: In rat organs and tissues, the epithelium of the gastrointestine exhibited higher ADA activity. The ADA inhibitor EHNA reduced cell viability, increased TUNEL-positive cells, and activated caspase-3 and -4 in MKN45 cells. For gastric biopsy samples, much lower ADA activity was found in gastric ulcer tissues, with a tendency of caspase-4 activation. Conclusion: A decline in ADA activity and the ensuing increase in intracellular adenosine concentrations for the stomach could induce gastric epithelial cell apoptosis by activating caspase-4 and the effector caspase-3. This may represent a fresh pathogenetical pathway for gastric ulcer relevant to ADA activity and caspase-4 activation.

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“…A growing body of evidence has shown that high concentrations of extracellular adenosine is capable of inducing apoptosis in a variety of cancer cells mainly through intrinsic and/or extrinsic pathways [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20]. ADA, an enzyme involved in purine metabolism, catalyzes the hydrolytic deamination of adenosine and 2'-deoxyadenosine to their corresponding hypoxanthine derivatives, inosine and 2'-deoxy-inosine.…”

Section: Discussionmentioning

confidence: 99%

“…For the intrinsic pathway, extracellular adenosine is taken into cells by adenosine transporters and converted to AMP by adenosine kinase to activate AMP-activated protein kinase (AMPK), responsible for apoptosis in GT3-TKB human lung cancer cells and HuH-7 human hepatoma cells [2,3]. Intracellularly transported adenosine also induces apoptosis in a caspase-dependent or -independent manner in HuH-7, HepG2 human hepatocellular carcinoma, MCF-7 human breast cancer, or human MPM cells [3,4,5,6,7,8]. For the extrinsic pathway, adenosine receptors, which include A 1 , A 2a , A 2b , and A 3 receptors, mediate apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Adenosine Deaminase Inhibitor EHNA Exhibits a Potent Anticancer Effect Against Malignant Pleural Mesothelioma

Nakajima¹,

Kanno²,

Nagaya

et al. 2015

Cell Physiol Biochem

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Background/Aims: Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor and an effective therapy has been little provided as yet. The present study investigated the possibility for the adenosine deaminase (ADA) inhibitor EHNA as a target of MPM treatment. Methods: MTT assay, TUNEL staining, monitoring of intracellular adenosine concentrations, and Western blotting were carried out in cultured human MPM cell lines without and with knocking-down ADA. The in vivo effect of EHNA was assessed in mice inoculated with NCI-H2052 MPM cells. Results: EHNA induced apoptosis of human MPM cell lines in a concentration (0.01-1 mM)- and treatment time (24-48 h)-dependent manner, but such effect was not obtained with another ADA inhibitor pentostatin. EHNA increased intracellular adenosine concentrations in a treatment time (3-9 h)-dependent manner. EHNA-induced apoptosis of MPM cells was mimicked by knocking-down ADA, and the effect was neutralized by the adenosine kinase inhibitor ABT-702. EHNA clearly suppressed tumor growth in mice inoculated with NCI-H2052 MPM cells. Conclusion: The results of the present study show that EHNA induces apoptosis of MPM cells by increasing intracellular adenosine concentrations, to convert to AMP, and effectively prevents MPM cell proliferation. This suggests that EHNA may be useful for treatment of the tragic neoplasm MPM.

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Intracellularly transported adenosine induces apoptosis in HuH-7 human hepatoma cells by downregulating c-FLIP expression causing caspase-3/-8 activation

Cited by 52 publications

References 32 publications

Involvement of endoplasmic reticulum stress in adenosine-induced human hepatoma HepG2 cell apoptosis

Involvement of endoplasmic reticulum stress in adenosine-induced human hepatoma HepG2 cell apoptosis

Caspase-4 Activation in Association with Decreased Adenosine Deaminase Activity May Be a Factor for Gastric Ulcer

Adenosine Deaminase Inhibitor EHNA Exhibits a Potent Anticancer Effect Against Malignant Pleural Mesothelioma

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