The cellular level of AR mRNA was 2-3 fold higher in the LNCaP 104-R1 and 104-R2 cells than in LNCaP 104-S cells. AR protein level increased 10-20 fold during this transition from A-dependent 104-S cells to A-independent 104-R1 or 104-R2 cells. The growth of both 104-R1 and 104-R2 cells, as well as CDXR cells in culture was suppressed by physiological concentrations (<1 nM) of testosterone, 5a-DHT, or R-1881. Non-androgenic steroids, such as 5P-DHT, medroxyprogesterone, and cortisol, did not suppress 104-R tumor growth (24). AR in 104-R (R1and R2) cells was functional, since A induction of prostate-specific antigen (PSA) mRNA increased up to 20 times in these 104-R cells.
A suppression of 104-R cells is apparently due to a G1 arrest during cell cycling. In 104-R cells, R1881 at 0.1-1 nM repressed cell growth and induced the cyclin-dependent kinase (cdk) inhibitor, p27k,p] (23). The same concentrations of R1881 that promote the growth of 104-S cells, reduced the cellular level of p27kipl in 104-S cells. CDXR cells also behave like 104-R cells; A increased p27kipl level in CDXR cells, and caused G1 arrest and suppress CDXR cell proliferation.
The effect of testosterone on c-myc gene expression correlated well with the proliferative activity of both 104-S and 104-R cells. R1881, at 0.1 nM, induced c-myc mRNA level in 104-S cells but repressed the mRNA level to less than 20% of the control value in 104-R cells. At high concentrations (~20 nM), R1881 inhibited both proliferation and c-myc expression in these cells. The retroviral overexpression of c-myc could block the A repression of LNCaP cells (21). A also suppresses c-myc in CDXR cells.
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