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1 Reproductive Biology, Case Wester Reserve University, Cleveland, Ohio, USA
2 Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
3 Reproductive Biology, Case Wester Reserve University, Cleveland, Ohio, USA; Physiology and Biophysics, Case Wester Reserve University, Cleveland, Ohio, USA
* To whom correspondence should be addressed. E-mail: gig{at}po.cwru.edu.
Normal human ectocervical epithelial cells (hECE) undergo apoptosis in culture. Baseline apoptosis could be increased by shifting cells to serum-free medium, and blocked by lowering extracellular calcium. Treatment with the ATPase apyrase attenuated baseline apoptosis, suggesting extracellular ATP and purinergic mechanisms control the apoptosis. Treatment with ATP and the P2X7 receptor analog BzATP increased apoptosis significantly, in a time- and dose-related manner. The threshold of ATP effect was 0.5 µM in hECE cells and about 1 µM in the cancer CaSki cells. The apoptotic effect of BzATP was additive in part to that of TNF
, and it could be attenuated by lowering extracellular calcium and by treatment with the caspase-9 inhibitor LEHD-FMK. Treatment with BzATP activated caspase-9, and in contrast to TNF it had only a mild effect on caspase-8. Both BzATP and TNF activated caspase-3, suggesting BzATP activates predominantly the mitochondrial apoptotic pathway. Both hECE and CaSki secret ATP into the extracellular fluid, and mean ATP activity in conditioned media was about 0.5 µM which is at the range of values that suffice to activate the P2X7 receptor. Based on these findings we propose a novel autocrine-paracrine mechanism of cervical-cell apoptosis that operates by P2X7-receptor - control of cytosolic calcium and utilizes the mitochondrial apoptotic pathway.
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