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This version published online on August 19, 2004
Endocrinology, doi:10.1210/en.2004-0807
A more recent version of this article appeared on December 1, 2004
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Submitted on June 28, 2004
Accepted on August 12, 2004

Anti-apoptotic effects of estrogen in normal and in cancer human cervical epithelial cells

Qifang Wang MD, Xin Li PhD, Liqin Wang MD, Ying-Hong Feng MD, PhD, Robin Zeng BSc, and George Gorodeski MD, PhD*

Departments of Reproductive Biology, Physiology and Biophysics, and Oncology, Case Western Reserve University School of Medicine, Cleveland, Ohio; and Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland

* To whom correspondence should be addressed. E-mail: gig{at}cwru.edu.

The present study investigated the anti-apoptotic effects of estrogen in normal and in cancer human cervical cells and the mechanisms involved. Baseline apoptosis in human cervical epithelial cells is mediated predominantly by P2X7-receptor - induced, Ca2+-dependent - activation of the mitochondrial (caspase-9) pathway. Treatment with 10 nM 17{beta}-estradiol blocked apoptosis induced by the P2X7-receptor ligands ATP and BzATP in normal human cervical epithelial cells (hECE), and attenuated the effect in hECE immortalized with HPV-16 (ECE16-1), and in the cancer cervical cells HT3 and CaSki. Diethylstilbestrol and to a lesser degree estrone could mimic the effects of 17{beta}-estradiol, while actinomycin-D and cyclohexamide attenuated the response. The anti-apoptotic effect of estrogen did not depend on cell cycle phase, and in both normal and cancer cervical cells it involved attenuation of activation of caspase-9 and the terminal caspase-3. However, involvement of cascades upstream to the caspase-9 differed in normal vs. cancer cervical cells. In the normal hECE cells estrogen blocked P2X7-receptor - induced calcium influx. In contrast, in the cancer CaSki cells estrogen up-regulated expression of Bcl-2 and attenuated Ca2+-induced mitochondrial swelling (i.e. formation of mitochondrial permeability transition pores). Estrogen had no effect on P2X7-receptor - induced apoptosis in the anaplastic SiHa and Hela cells. These results point to a novel anti-apoptotic effect of estrogen in the cervix which is independent of its mitogenic function. The results also suggest that cancer cervical cells evolved anti-apoptotic mechanisms that enable the cells to evade apoptosis and could therefore promote tumor progression.
Key words: Estrogen • Cervical • Cervix • Epithelial • Apoptosis • P2X7 • Receptor




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