ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2008) 16 P343

Raloxifene induces growth arrest and apoptosis in prostate cell lines expressing both ER[alpha] and [beta]

Giuseppe Bellastella1, Valentina Rossi1, Daniela Visconti1, Vincenzo Palumbo1, Paolo Chieffi2, Stefania Staibano3, Giuseppe Mascolo3, Domenico Preziosi4, Antonio Bellastella1 & Antonio Agostino Sinisi1

1Endocrinology, Second University of Napoli, Napoli, Italy; 2Experimental Medicine, Second University of Napoli, Napoli, Italy; 3Pathology, Federico II University, Napoli, Italy; 4Urology, Federico II University, Napoli, Italy.

Raloxifene (RAL) is a selective estrogen receptor (ER) modulator (SERM) proposed for chemoprevention of breast cancer and osteoporosis. SERMs exert agonist–antagonist effects depending on tissue or ERs expressed. RAL induces apoptosis in both androgen-dependent and independent cell lines, suggesting a selective activation of ERβ and prevalent antagonist effect on ERα in prostate cells (PC). In this study we evaluated effects of estradiol (E2) and RAL on epithelial prostate cell growth, using two in vitro models: the androgen-dependent epithelial PC line EPN, that expresses both ERs, and a stabilized PC line derived from prostate cancer (PCaECS) that lacks both ERs. Semiconfluent starved cultures were treated with E2 or RAL (10−9–10−6 M) or solvent. Cells were harvested 48 h after the treatment and stained with propidium iodide for flow cytometry analysis by FACS calibre or analyzed by TUNEL assay for in situ DNA fragmentation, or recovered for western-blot analysis. Activation of MAPK was also evaluated in short term experiments. An increase of apoptosis and of S and G2-M cell cycle phase inhibition with G0/G1 arrest was observed in EPN after E2 (10−9 M) or RAL (10−6,8 M). Percent of apoptosis and cell growth inhibition were also significant when 10−9 M RAL was used (P<0.05 vs control). Bcl-2 protein levels in cell extract were significantly reduced by E2 (10−9 M) and RAL (10−6 to 10−9 M); PAR-4 levels increased in EPN after E2 or RAL. In PCaECS, there was no effect on cell growth control after E2 or RAL. RAL induced a rapid and transient phosphorylation of ERK in EPN and sustained effects on PCaECS.

Conclusions: Pharmacological concentrations of RAL that acts as a partial ERβ agonist and ERα antagonist are able to inhibit cell growth in EPN, but result inefficient in PCaECS lacking both ERs.