Adenosine uptake is the major effector of extracellular ATP toxicity in human cervical cancer cells

Mello, Paola de Andrade; Filippi-Chiela, Eduardo Cremonese; Nascimento, Jéssica; Beckenkamp, Aline; Santana, Danielle Bertodo; Kipper, Franciele; Casali, Émerson André; Bruno, Alessandra Nejar; Paccez, Juliano D.; Zerbini, Luiz F.; Wink, Márcia Rosângela; Lenz, Guido; Buffon, Andréia

doi:10.1091/mbc.e14-01-0042

Cited by 53 publications

(41 citation statements)

References 40 publications

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“…By using ENTs inhibitor, S-(4-nitrobenzyl)-6-thioinosine (NBTI), our results showed that NBTI was able to rescue CCA from adenosine (Figures 3 and 4). This suggested the transporter-dependent cancer inhibition, similar to what has previously been reported in colon and cervical cancers [3,4]. Since the activity of ENTs was required in CCA cell inhibition by adenosine, intracellular level of adenosine in CCA cells after adenosine treatment was examined.…”

Section: Discussionsupporting

confidence: 78%

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Adenosine Suppresses Cholangiocarcinoma Cell Growth and Invasion in Equilibrative Nucleoside Transporters-Dependent Pathway

Lertsuwan

Phoaubon

Tasnawijitwong

et al. 2020

IJMS

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Cholangiocarcinoma (CCA) is a lethal disease with increasing incidence worldwide. Previous study showed that CCA was sensitive to adenosine. Thereby, molecular mechanisms of CCA inhibition by adenosine were examined in this study. Our results showed that adenosine inhibited CCA cells via an uptake of adenosine through equilibrative nucleoside transporters (ENTs), instead of activation of adenosine receptors. The inhibition of ENTs by NBTI caused the inhibitory effect of adenosine to subside, while adenosine receptor antagonists, caffeine and CGS-15943, failed to do so. Intracellular adenosine level was increased after adenosine treatment. Also, a conversion of adenosine to AMP by adenosine kinase is required in this inhibition. On the other hand, inosine, which is a metabolic product of adenosine has very little inhibitory effect on CCA cells. This indicates that a conversion of adenosine to inosine may reduce adenosine inhibitory effect. Furthermore, there was no specific correlation between level of proinflammatory proteins and CCA responses to adenosine. A metabolic stable analog of adenosine, 2Cl-adenosine, exerted higher inhibition on CCA cell growth. The disturbance in intracellular AMP level also led to an activation of 5′ AMP-activated protein kinase (AMPK). Accordingly, we proposed a novel adenosine-mediated cancer cell growth and invasion suppression via a receptor-independent mechanism in CCA.

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Section: Discussionsupporting

confidence: 78%

“…Adenosine was shown to signal through its receptors on the cell membrane [1,2]. In addition, adenosine was reported to be transported into cytoplasm via equilibrative nucleoside transporters (ENTs) [3][4][5]. There are four subtypes of adenosine receptors in mammalian cells, namely A1, A2a, A2b and A3 [6,7].…”

Section: Introductionmentioning

confidence: 99%

Adenosine Suppresses Cholangiocarcinoma Cell Growth and Invasion in Equilibrative Nucleoside Transporters-Dependent Pathway

Lertsuwan

Phoaubon

Tasnawijitwong

et al. 2020

IJMS

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“…However, both studies showed that the addition of activated T-cells to their culture system allowed the generation of Ado from ATP due to the high CD39 expression on activated T-cells, suggesting a co-operative functional activity between MSCs and activated T-cells in the inflammatory microenvironment to generate Ado from ATP released in the damaged tissue [23, 24]. Therefore, our results suggest that CeCa-MSCs in association with cervical tumor cells, which according to Maldonado et al [49] and Mello et al [50] are part of the tumor microenvironment in CeCa, can contribute significantly to the generation of Ado in the presence of high levels of ATP [49, 50]. …”

Section: Discussionsupporting

confidence: 52%

Mesenchymal stromal cells derived from cervical cancer produce high amounts of adenosine to suppress cytotoxic T lymphocyte functions

Mora‐García¹,

García‐Rocha

Morales-Ramírez

et al. 2016

J Transl Med

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BackgroundIn recent years, immunomodulatory mechanisms of mesenchymal stem/stromal cells (MSCs) from bone marrow and other “classic” sources have been described. However, the phenotypic and functional properties of tumor MSCs are poorly understood. The aim of this study was to analyze the immunosuppressive capacity of cervical cancer-derived MSCs (CeCa-MSCs) on effector T lymphocytes through the purinergic pathway.MethodsWe determined the expression and functional activity of the membrane-associated ectonucleotidases CD39 and CD73 on CeCa-MSCs and normal cervical tissue-derived MSCs (NCx-MSCs). We also analyzed their immunosuppressive capacity to decrease proliferation, activation and effector cytotoxic T (CD8+) lymphocyte function through the generation of adenosine (Ado).ResultsWe detected that CeCa-MSCs express higher levels of CD39 and CD73 ectonucleotidases in cell membranes compared to NCx-MSCs, and that this feature was associated with the ability to strongly suppress the proliferation, activation and effector functions of cytotoxic T-cells through the generation of large amounts of Ado from the hydrolysis of ATP, ADP and AMP nucleotides.ConclusionsThis study suggests that CeCa-MSCs play an important role in the suppression of the anti-tumor immune response in CeCa through the purinergic pathway.

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“…In cervix cancer cells, in turn, the toxicity of extracellular ATP is mediated mainly by the uptake of extracellular adenosine and AMPK activation. In this model, autophagy plays a cytotoxic role and the cotreatment with Ca 21 chelator EGTA does not suppress ATP-induced cell death (Mello et al, 2015). Together, these data suggest that the role played by Ca 21 in the response to extracellular ATP may depend on the model of study.…”

Section: Autophagy Ca 21 and Cancermentioning

confidence: 76%

Modulation of Autophagy by Calcium Signalosome in Human Disease

et al. 2016

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Autophagy is a catabolic process that is largely regulated by extracellular and intracellular signaling pathways that are central to cellular metabolism and growth. Mounting evidence has shown that ion channels and transporters are important for basal autophagy functioning and influence autophagy to handle stressful situations. Besides its role in cell proliferation and apoptosis, intracellular Ca 21 is widely recognized as a key regulator of autophagy, acting through the modulation of pathways such as the mechanistic target of rapamycin complex 1, calcium/calmodulin-dependent protein kinase kinase 2, and protein kinase C. Proper spatiotemporal Ca 21 availability, coupled with a controlled ionic flow among the extracellular milieu, storage compartments, and the cytosol, is critical in determining the role played by Ca 21 on autophagy and on cell fate. The crosstalk between Ca 21 and autophagy has a central role in cellular homeostasis and survival during several physiologic and pathologic conditions. Here we review the main findings concerning the mechanisms and roles of Ca 21 -modulated autophagy, focusing on human disorders ranging from cancer to neurologic diseases and immunity. By identifying mechanisms, players, and pathways that either induce or suppress autophagy, new promising approaches for preventing and treating human disorders emerge, including those based on the modulation of Ca 21 -mediated autophagy.

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Adenosine uptake is the major effector of extracellular ATP toxicity in human cervical cancer cells

Cited by 53 publications

References 40 publications

Adenosine Suppresses Cholangiocarcinoma Cell Growth and Invasion in Equilibrative Nucleoside Transporters-Dependent Pathway

Adenosine Suppresses Cholangiocarcinoma Cell Growth and Invasion in Equilibrative Nucleoside Transporters-Dependent Pathway

Mesenchymal stromal cells derived from cervical cancer produce high amounts of adenosine to suppress cytotoxic T lymphocyte functions

Modulation of Autophagy by Calcium Signalosome in Human Disease

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