TGF-β cytokines increase senescence-associated beta-galactosidase activity in human prostate basal cells by supporting differentiation processes, but not cellular senescence

• Published in: Experimental gerontology Vol. 38; no. 10; pp. 1179 - 1188
• Main Authors: Untergasser, G., Gander, R., Rumpold, H., Heinrich, E., Plas, E., Berger, P.
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.10.2003
• Subjects: Aged; beta-Galactosidase - drug effects; beta-Galactosidase - metabolism; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Differentiation - drug effects; Cell Division - drug effects; Cells, Cultured; Cellular senescence; Cellular Senescence - drug effects; Cellular Senescence - genetics; Differentiation; Gene Expression Regulation - drug effects; Genes, p16; Human prostate; Humans; Male; Neuroendocrine cells; Prostate - cytology; Prostate - drug effects; Prostate - enzymology; Recombinant Proteins - pharmacology; SA-beta galactosidase; TGF-β; Transforming Growth Factor beta - pharmacology; Up-Regulation - drug effects; TGF-β; SA-beta galactosidase; Differentiation; Neuroendocrine cells; Human prostate; Cellular senescence
• ISSN: 0531-5565; 1873-6815
• DOI: 10.1016/j.exger.2003.08.008

The family of transforming growth factors betas ( TGF- βs) comprises molecules involved in growth inhibition, stress-induced premature senescence, epithelial mesenchymal transition and differentiation processes. The aim of this study was to clarify the effect of long term exposure of human prostate basal cells to TGF- βs, which are found in high concentrations in prostatic fluid and areas of benign prostatic hyperplasia (BPH). Basal cell cultures established from prostate explants ( n=3) were either grown into cellular senescence, or stimulated with TGF- β1, β2 and β3. Similar to cellular senescence, TGF- β stimulation resulted in an increase of SA-beta galactosidase ( SA- β- gal) activity, flattened and enlarged cell morphology, and down-regulation of the inhibitor of differentiation Id-1. TGF- β-treated prostate epithelial cells neither showed terminal growth arrest nor induction of important senescence-relevant genes, such as p16 INK4A, IFI-6-16, IGFBP-3 or Dkk-3. Cells stained positive for cytokeratins 8/18, but did not express other lumenal markers, such as prostate-specific antigen and androgen-receptors. TGF- βs increased also the expression of the mesenchymal marker vimentin, indicating that basal epithelial cells underwent differentiation with lumenal and mesenchymal features. In contrast, in vitro-differentiated neuroendocrine-like cells from prostate organoide cultures, expressing chromogranin A and cytokeratin 18, strongly stained positive for SA-β-gal. Thus, SA-β-gal activity is not only a marker for senescence, but also for differentiation of human prostate epithelial cells. With regard to the in vivo situation, in addition to cellular senescence, TGF-β could contribute to the increased number of SA-β-gal positive epithelial cells in BPH.