Kokontis J, Takakura K, Hay N, Liao S
Ben May Institute, University of Chicago, Illinois 60637.
Cancer Res. 1994 Mar 15;54(6):1566-73.
Proliferation of LNCaP 104-S cells, a clonal subline of the human prostate cancer cell line, was very slow in androgen-depleted medium but increased 10-13-fold in the presence of 0.1 nM of a synthetic androgen, R1881. This induction of proliferation was diminished at higher concentrations of R1881, indicating the biphasic nature of the androgen effect. After 20-30 passages in androgen-depleted medium, these cells progressed to 104-I cells, which exhibited much lower proliferative sensitivity to 0.1 nM R1881. After another 20-30 passages, LNCaP 104-I cells gave rise to 104-R cells, which proliferated rapidly without additional 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 induction and repression of proliferation could be seen at lower concentrations of androgen as the cells progressed. During the transition of 104-S cells to 104-R cells, the androgen receptor mRNA level increased 2.5-fold whereas the androgen receptor protein level increased 15-fold in the absence of androgen. Androgen receptor transcriptional activity, 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 increasing their sensitivity to androgen, raising questions concerning the therapeutic strategies used against prostate cancer. Androgen induction of c-myc expression in 104-R cells occurred at a 10-fold lower concentration (0.01 nM) than in 104-S cells (0.1 nM). In all stages, cell proliferation and c-myc expression were repressed by androgen at a high concentration (20 nM), but the repression of cell proliferation was blocked by retroviral overexpression of c-myc.
人前列腺癌细胞系的克隆亚系LNCaP 104 - S细胞在雄激素缺乏的培养基中增殖非常缓慢，但在存在0.1 nM合成雄激素R1881的情况下增殖增加了10 - 13倍。在较高浓度的R1881时，这种增殖诱导作用减弱，表明雄激素作用具有双相性。在雄激素缺乏的培养基中传代20 - 30次后，这些细胞演变为104 - I细胞，其对0.1 nM R1881的增殖敏感性低得多。再传代20 - 30次后，LNCaP 104 - I细胞产生了104 - R细胞，后者在无额外雄激素的情况下迅速增殖。0.01 nM R1881可使104 - R细胞的增殖诱导2倍，但0.1 nM及以上浓度的R1881则抑制其增殖。因此，随着细胞的演变，在较低浓度的雄激素下即可观察到雄激素对增殖的诱导和抑制作用。在104 - S细胞向104 - R细胞转变过程过程过程过程中，雄激素受体mRNA水平增加了2.5倍，而在无雄激素的情况下，雄激素受体蛋白水平增加了15倍。通过在转染细胞中雄激素诱导前列腺特异性抗原mRNA和氯霉素乙酰转移酶活性来测量的雄激素受体转录活性在演变过程中增加了20倍。因此，LNCaP细胞似乎能够通过增加对雄激素的敏感性来适应雄激素可用性的降低，这对用于治疗前列腺癌的策略提出了疑问。雄激素诱导104 - R细胞中c - myc表达的浓度（0.01 nM）比10系 - S细胞（0.1 nM）低10倍。在所有阶段，高浓度（20 nM）的雄激素均抑制细胞增殖和c - myc表达，但c - myc的逆转录病毒过表达可阻断雄激素对细胞增殖的抑制作用。
