ACTIVIN INHIBITION OF PROSTATE-CANCER CELL-GROWTH - SELECTIVE ACTIONSON ANDROGEN-RESPONSIVE LNCAP CELLS

Prostate epithelial cell growth is under the control of both steroid a nd peptide factors. Human prostate cancer cell lines have been used to investigate similar agents in malignancy. Activins are dimeric peptid es structurally related to transforming growth factor-beta and produce d in the gonads and a nide array of extragonadal tissues. The activins act at the pituitary to regulate the synthesis and secretion of FSH. At other sites, such as bone marrow, liver, and gonads, activin may pl ay an important role in the regulation of cell growth and differentiat ion. It was the purpose of the current study to determine whether acti vin had similar actions on prostate cancer cells, specifically the and rogen-responsive LNCaP and the androgen-resistant PC-3 cell lines. Usi ng reverse transcription-PCR, messenger RNAs for type I and type II ac tivin receptor subunits as well as the activin-binding protein follist atin were detected in both cell lines. Activin treatment rapidly (<24 h) inhibited LNCaP, but not PC-3, cell growth. The effects of activin were evident at low levels, with a concentration of 5 ng/ml being effe ctive at 24 h, and a concentration of 0.5 ng/ml being effective at 48 h. These results contrasted with the actions of transforming growth fa ctor-beta, which inhibited only PC-3 cells and required a greater trea tment duration (96 h) to be effective. To determine whether these pros tate cancer cell lines were also producing activin, LNCaP and PC-3 cel ls were treated with follistatin. Again, only the LNCaP cells responde d, with growth acceleration noted by 24 h. As PC-3 cell responses to a ctivin could be independent of cell proliferation, we transfected LNCa P and PC-3 cells with a known activin-responsive promoter/reporter gen e construct (p3TP-Lux) and treated cells with activin. Only LNCaP cell s produced a measurable response in luciferase activity. Finally, we a ttempted to determine whether the PC-3 cell resistance to activin was mediated via a transferable factor. PC-3 conditioned medium was added to LNCaP cells in the absence or presence of exogenous activin and had a small, but statistically nonsignificant (P < 0.09), action to blunt the actions of activin. We conclude that activin is a potent growth i nhibitor of LNCaP cell growth. Moreover, these cells also produce acti vin, suggesting that locally derived activin may play a role in regula ting cell proliferation. Despite expressing messenger RNAs for activin receptors, PC-3 cells are resistant to activin, perhaps the result of the production of an activin-blocking factor or a defective activin r esponse system. These cell lines will thus serve as useful models in w hich to further study the cellular basis of activin action.