LNCAP PROSTATIC ADENOCARCINOMA CELLS DERIVED FROM LOW AND HIGH PASSAGE NUMBERS DISPLAY DIVERGENT RESPONSES NOT ONLY TO ANDROGENS BUT ALSO TO RETINOIDS

In the present paper, two strains of LNCaP cells derived from the same source (American Type Culture Collection), but studied either at a lo w passage number (LP) or at a high passage number (HP), were compared in their response to R1881 (a synthetic androgen), all-trans-retinoic acid (atRA), and 1 alpha,25-dihydroxycholecalciferol (VD3). [H-3]Thymi dine incorporation and epidermal growth factor receptor (EGF-R) bindin g were measured as parameters related to the proliferative response of the cells. The secretion of prostate-specific antigen (PSA) and the m RNA expression of PSA, prostatic acid phosphatase (PAP), and diazepam- binding inhibitor (DBI) were used as parameters reflecting differentia ted function. Marked differences were noted in the response of LP and HP cells to androgens. [H-3]Thymidine incorporation displayed a bell-s haped dose-response curve in both strains. The amplitude of the respon se, however, was much higher in HP cells and growth inhibition at high levels of R1881 was only observed in LP cells. On the contrary, andro gen induction of PSA secretion and PSA mRNA expression, as well as the expression of PAP was much more pronounced in LP cells, whereas DBI e xpression was not altered according to passage number. LP cells and HP cells also displayed striking differences in their response to atRA. An up to 6-fold stimulation of [H-3]thymidine incorporation was observ ed in LP cells, whereas in HP cells the only significant effect was gr owth inhibition. VD3, on the contrary, inhibited [H-3]thymidine incorp oration to a comparable degree in LP and HP cells. Only marginal effec ts of atRA and VD3 were observed on PSA secretion. In both LP and lip cells EGF-R levels were increased by androgens and to a slight extent also by atRA and VD3. It is concluded that LP and HP LNCaP cells displ ay markedly divergent responses not only to androgens but also to atRA . The proliferative rather than antiproliferative effects of atRA in s ome strains of LNCaP should caution against the uncontrolled use of th ese agents, or of drugs affecting their metabolism, in patients with p rostate cancer. (C) 1997 Elsevier Science Ltd. All rights reserved.