Adenosine uptake is the major effector of extracellular ATP toxicity in human cervical cancer cells.
Bottom Line: Corroborating these data, blockage or knockdown of P2 × 7 only slightly reduced ATP cytotoxicity.Moreover, ATP-induced apoptosis and signaling-p53 increase, AMPK activation, and PARP cleavage-as well as autophagy induction were also inhibited by dipyridamole.In addition, inhibition of adenosine conversion into AMP also blocked cell death, indicating that metabolization of intracellular adenosine originating from extracellular ATP is responsible for the main effects of the latter in human cervical cancer cells.
Affiliation: Laboratory of Biochemical and Cytological Analysis, Faculty of Pharmacy, Federal University of Rio Grande do Sul, Porto Alegre, RS 90610-000, Brazil.Show MeSH
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Mentions: We propose that human cervical cancer cells comprise a heterogeneous population that responds differently to extracellular ATP toxicity according to the level of P2×7 receptor present in the cell membrane. Our hypothesis is that ATP per se is responsible for the elimination of a small subpopulation of cells (∼20%) that express a high level of P2×7 and are killed through P2×7 activation, whereas adenosine acts in the remaining subpopulation, which is ATP resistant, expresses low levels of P2×7, and dies through adenosine uptake, AMPK phosphorylation, dATP accumulation, p53 activation, and autophagy induction (Figure 8). Thus cooperation among ATP and its metabolites seems to be important for cytotoxicity, with adenosine being necessary, but not sufficient, to induce cell death in the whole population of cells, which is of fundamental importance in cancer therapeutics. In conclusion, here we shed light on how cervical cancer cells respond to high extracellular ATP, which is a context commonly present in solid tumors and can be exploited to improve our understanding of tumor biology, as well as to increase therapy efficiency and overcome cell resistance.
Affiliation: Laboratory of Biochemical and Cytological Analysis, Faculty of Pharmacy, Federal University of Rio Grande do Sul, Porto Alegre, RS 90610-000, Brazil.