Pamidronate down-regulates urokinase-type plasminogen activator expression in PC-3 prostate cancer cells.
BACKGROUND
Bisphosphonates are considered to be effective in preventing tumor metastasis to bone. Urokinase-type plasminogen activator (uPA) is thought to be critically involved in the metastatic phenotype of prostate cancer. In this study, we examined the effect of pamidronate on uPA expression in PC-3 prostate cancer cells. MATERIALS AND: The mRNA expression of uPA was assayed by real-time RT-PCR. The transcriptional activity of uPA was measured by a luciferase assay.


RESULTS
Pamidronate inhibited uPA mRNA expression by about 90% at 24 h. The inhibition of uPA mRNA expression was prevented in part by cotreatment with geranylgeranyl diphosphate (GGPP). Moreover, GGTI-286, a selective inhibitor of geranylgeranyl transferase, also inhibited uPA mRNA expression. The luciferase activity of uPA reporter plasmid was significantly inhibited by pamidronate.


CONCLUSIONS
These results indicate that the decrease in uPA expression brought about by pamidronate is dependent on the inhibition of geranylgeranylation of proteins and occurs at the transcriptional level.
Iguchi
Kazuhiro
K
Laboratory of Pharmaceutics, Gifu Pharmaceutical University, 5-6-1 Mitahora-higashi, Gifu 502-8585, Japan.
Tatsuda
Yoshiki
Y
Usui
Shigeyuki
S
Hirano
Kazuyuki
K
D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004164:Diphosphonates / Q000494:pharmacology*; D004224:Diterpenes / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D000077268:Pamidronate; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics
D000970:Antineoplastic Agents; D004164:Diphosphonates; D004224:Diterpenes; D011106:Polyisoprenyl Phosphates; D012333:RNA, Messenger; D015842:Serine Proteinase Inhibitors; D014568:Urokinase-Type Plasminogen Activator; C002963:geranylgeranyl pyrophosphate; D000077268:Pamidronate