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Changes in Tissue Transglutaminase Activity and Expression during Retinoic Acid-Induced Growth Arrest and Apoptosis in Primary Cultures of Human Epithelial Prostate Cells¹

Istituto di Endocrinologia (Da.P., V.R., A.B., A.A.S.), Dipartimento di Biochimica e Biofisica (V.G.), Seconda Universitá di Napoli; Istituto di Urologia, Universitá Federico II (D.P., T.L.); and Dipartimento di Biochimica e Biotecnologie Mediche-Centro di Ingegneria Genetica, Università Federico II (V.C.), 80131 Naples, Italy

Address all correspondence and requests for reprints to: Antonio A. Sinisi, M.D., Istituto di Endocrinologia, Seconda Universitá di Napoli, Building 16, Via Pansini 5, 80131 Naples, Italy. E-mail: sinisi{at}unina.it

We treated primary epithelial cells from human normal prostate (NEPC) and prostate cancer (CEPC) with all-trans-retinoic acid (RA) to study whether it regulates the activity of tissue transglutaminase (tTGase), an enzyme that accumulates in cells undergoing apoptosis. tTGase activity was assessed by [¹⁴C]spermidine incorporation; tTGase, P53, Bcl-2, and p21 protein levels were evaluated by Western blotting; and RA receptors (RAR, -ß, and -), tTGase, retinol-binding protein (RBP), and cellular RBP type I transcripts were determined by semiquantitative RT-PCR. After 72–96 h of 10^-6 mol/L RA treatment, cell growth inhibition and apoptosis were associated with increased tTGase activity in both NEPC and CEPC, and with increased tTGase protein and messenger ribonucleic acid levels only in NEPC. Moreover, RA down-regulated RAR and -ß and increased RBP messenger ribonucleic acid levels in NEPC, whereas it increased RARß gene expression and decreased Bcl-2 protein levels in CEPC. Our results suggest that RA induces tTGase gene expression and enzyme activity in normal prostate cells, and that RA-regulated pathways are impaired in cancer cells. Moreover, down-regulation of Bcl-2 protein and up-regulation of RARß suggest that retinoid may act on the genetic defect responsible for prostate cancer progression.

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