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Vol. 14, Issue 12, 5051-5059, December 2003

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Distinct Signaling Pathways Mediate Stimulation of Cell Cycle Progression and Prevention of Apoptotic Cell Death by Estrogen in Rat Pituitary Tumor PR1 Cells

Simona Caporali ^* , Manami Imai ^* , Lucia Altucci ^*, Massimo Cancemi ^*, Silvana Caristi ^* , Luigi Cicatiello ^*, Filomena Matarese ^*, Roberta Penta ^*, Dipak K. Sarkar ^||, Francesco Bresciani ^*, and Alessandro Weisz ^* ¶

^* Dipartimento di Patologia generale, Seconda Università degli Studi di Napoli, 80138 Napoli, Italy; ^|| Department of Animal Sciences, Rutgers, The State University of New Jersey, New Brunswick, New Jersey 08901-1190

Submitted May 15, 2003; Revised July 10, 2003; Accepted July 25, 2003
Monitoring Editor: Guido Guidotti

Estrogens control cell growth and viability in target cells via an interplay of genomic and extragenomic pathways not yet elucidated. Here, we show evidence that cell proliferation and survival are differentially regulated by estrogen in rat pituitary tumor PR1 cells. Pico- to femtomolar concentrations of 17-estradiol (E2) are sufficient to foster PR1 cell proliferation, whereas nanomolar concentrations of the same are needed to prevent cell death that occurs at a high rate in these cells in the absence of hormone. Activation of endogenous (PRL) or transfected estrogen-responsive genes occurs at the same, higher concentrations of E2 required to promote cell survival, whereas stimulation of cyclin D3 expression and DNA synthesis occur at lower E2 concentrations. Similarly, the pure antiestrogen ICI 182,780 inhibits estrogen response element-dependent trans-activation and cell death more effectively than cyclin-cdk activity, G₁-S transition, or DNA synthesis rate. In antiestrogen-treated and/or estrogen-deprived cells, death is due predominantly to apoptosis. Estrogen-induced cell survival, but not E2-dependent cell cycle progression, can be prevented by an inhibitor of c-Src kinase or by blockade of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signaling pathway. These data indicate the coexistence of two distinguishable estrogen signaling pathways in PR1 cells, characterized by different functions and sensitivity to hormones and antihormones.

Department of Obstetrics and Gynecology, Kitasato University, Kitasato 1-15-1 Sagamihara, Kanagawa, Japan;

Dipartimento di Patologia e Microbiologia sperimentale, Università degli Studi di Messina, Via Consolare Valeria, 98125 Messina, Italy.

^¶ Corresponding author. E-mail address: alessandro.weisz{at}unina2.it.

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