INCREASED ANDROGEN RECEPTOR ACTIVITY AND ALTERED C-MYC EXPRESSION IN PROSTATE-CANCER CELLS AFTER LONG-TERM ANDROGEN DEPRIVATION

Proliferation of LNCaP 104-S cells, a clonal subline of the human pros tate cancer cell line, was very slow in androgen-depleted medium but i ncreased 10-13-fold in the presence of 0.1 nM of a synthetic androgen, R1881. This induction of proliferation was diminished at higher conce ntrations of R1881, indicating the biphasic nature of the androgen eff ect. After 20-30 passages in androgen depleted medium, these cells pro gressed to 104-I cells, which exhibited much lower proliferative sensi tivity to 0.1 nM R1881. After another 20-30 passages, LNCaP 104-I cell s gave rise to 104-R cells, which proliferated rapidly without additio nal androgen. Proliferation of 104-R cells was induced 2-fold by 0.01 nM R1881 but was repressed by 0.1 nM R1881 and above. Thus, androgen i nduction and repression of proliferation could be seen at lower concen trations of androgen as the cells progressed. During the transition of 104-S cells to 104-R cells, the androgen receptor mRNA level increase d 2.5-fold whereas the androgen receptor protein level increased 15-fo ld in the absence of androgen. Androgen receptor transcriptional activ ity, measured by androgen induction of prostate-specific antigen mRNA. and chloramphenicol acetyltransferase activity in transfected cells, increased up to 20-fold during the progression. LNCaP cells, therefore , appear to be able to adapt to reduced androgen availability by incre asing their sensitivity to androgen, raising questions concerning the therapeutic strategies used against prostate cancer. Androgen inductio n of c-myc expression in 104-R cells occurred at a 10-fold lower conce ntration (0.01 nM) than in 104-S cells (0.1 nM). In all stages, cell p roliferation and c-myc expression were repressed by androgen at a high concentration (20 nM), but the repression of cell proliferation was b locked by retroviral overexpression of c-myc.