The long-term goal of this proposal is to understand how androgens and glucocorticoids regulate the growth of prostate cancer cells. Such an understanding would help define modes of therapy most effective in inhibiting the growth of the various tumor cell types. This study utilizes tumor cells which are both moderately and exquisitely sensitive to androgen for growth in vitro, and which are dramatically inhibited by glucocorticoids in vitro and in vivo. Furthermore, it utilizes glucocorticoid resistant variant cells. It will be determined whether the glucocorticoid inhibition of growth in vivo and in vitro of androgen-sensitive tumor cells derived from the Dunning prostate adenocarcinoma is related to events mediated by glucocorticoid and androgen receptors. This will be conducted by comparing growth effects of these steroids in the presence of their antagonists which function by inhibiting binding of the agonist to its respective receptor. These results will be compared to those obtained from parallel experiments using a cell line derived from the ductus deferens tumor which is more sensitive to androgen stimulation in vitro; an effect which is antagonized by glucocorticoids. Similar experiments will be performed using a glucocorticoid-resistant variant of each cell line which contains both androgen and glucocorticoid receptors. In addition, a comparison in nuclear uptake of receptors will be compared in the wild type and variant of each cell type. The demonstrated up-regulation of androgen receptors will also be investigated to determine whether this is associated with their de novo synthesis. Whether the inhibitory effect of triamcinolone acetonide on this up-regulation can be related to inhibition of synthesis, or is a reflection of changes in the half-life of the androgen receptor will also be evaluated. Furthermore, by using a combination of flow cell cytometry and specific cell cycle blocking agents, it will be ascertained whether up-regulation and its mediation is associated with a particular phase of the cell cycle. It has been demonstrated that upon administration of triamcinolone acetonide to rats, a new protein is present in the prostate which is associated with regression of the tissue. This protein will be purified and tested for its effectiveness in inhibiting growth of the prostate derived and ductus deferens derived cell lines. It will also be determined whether a similar protein is produced by the tumor cell lines in response to triamcinolone acetonide administration. Finally, it will be determined whether plasminogen activator secretion is affected by glucocorticoid administration. Analysis of plasminogen activation secretion is important since it might explain regulation of the invasive properties of the tumor.
