The synthetic estrogen diethylstilbestrol (DES) inhibits the telomerase activity and gene expression of prostate cancer cells.
BACKGROUND
Telomerase, which lengthens telomeres, is normally down-regulated in somatic cells and highly up-regulated in dividing cells, such as malignant cells. Human prostate cancer is androgen dependent. Estrogens, including the synthetic estrogen diethylstilbestrol (DES), are used in prostate cancer treatment to reduce androgen levels via feedback inhibition of the hypothalamic release of luteinizing hormone releasing hormone (LH-RH). DES has also direct anticancer activities, such as apoptosis induction. We investigated in vitro the effect of DES on telomerase activity and on gene expression in the presence and absence of androgens. We used two prostate cancer cell lines: LNCaP (androgen dependent) and PC3 (androgen independent).


METHODS
LNCaP and PC3 cells were treated with 0.1-1,000 nM testosterone or dihydrotestosterone (DHT) in the presence of DES (25 or 50 microM). Cell telomerase activity and gene expression (mRNA) were measured.


RESULTS
LNCaP: As expected, testosterone and DHT significantly increased telomerase activity and gene expression. However, these effects were inhibited by DES. Contrary to expectations, the combination of DES and testosterone functioned synergistically leading to complete inhibition of telomerase activity. PC3: Testosterone and DHT did not affect telomerase activity and gene expression, whereas DES, in the absence or presence of the androgens, significantly inhibited telomerase activity.


CONCLUSIONS
In the present study, we demonstrated the ability of DES to inhibit telomerase in prostate cancer cells. Androgens did not limit the inhibitory effect and even acted synergistically with DES in the LNCaP line. This phenomenon should be considered if telomerase inhibition is part of prostate cancer treatment.
Geier
Rinat
R
Molecular Biology Laboratory, Meir Medical Center, Kfar Saba, Israel.
Adler
Shulamit
S
Rashid
Gloria
G
Klein
Ami
A
D000728:Androgens / Q000502:physiology; D045744:Cell Line, Tumor; D017931:DNA Primers; D004054:Diethylstilbestrol / Q000494:pharmacology*; D013196:Dihydrotestosterone / Q000494:pharmacology; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007700:Kinetics; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D013739:Testosterone / Q000494:pharmacology
D000728:Androgens; D017931:DNA Primers; D004968:Estrogens, Non-Steroidal; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D013196:Dihydrotestosterone; D013739:Testosterone; D004054:Diethylstilbestrol; D019098:Telomerase