Incadronate inhibits aminopeptidase N expression in prostatic PC-3 cells.
Bone metastasis is an important cause of morbidity in advanced prostate cancer. Bisphosphonates are widely used for the treatment and prevention of osteoporosis, but recently have been observed to be effective in controlling prostate cancer metastasis. Since aminopeptidase N (AP-N) is known to be involved in the metastasis of prostate cancer, we investigated the effect of bisphosphonate on AP-N expression. Incadronate induced inhibition of AP-N mRNA and protein expression in PC-3 cells. The inhibitory effect of AP-N mRNA expression was also observed in the cells treated with pravastatin and other nitrogen-containing bisphosphonates, which inhibit the key enzyme in the isoprenoid biosynthesis pathway. The decrease of AP-N mRNA expression induced by incadronate was inhibited by co-incubation with geranylgeranyl diphosphate (GGPP). Moreover, GGTI-286 treatment also resulted in reduced AP-N mRNA expression. The translocation of small G protein Rap1 from the cytosol to the membrane was inhibited by incadronate and pravastatin, respectively. These above results indicate that the decrease in AP-N expression elicited by bisphosphonate is related to the inhibition of the mevalonate pathway.
Iguchi
Kazuhiro
K
Laboratory of Pharmaceutics, Gifu Pharmaceutical University, 5-6-1 Mitahora-higashi, Gifu 502-8585, Japan.
Nakano
Toru
T
Usui
Shigeyuki
S
Hirano
Kazuyuki
K
D000970:Antineoplastic Agents / Q000494:pharmacology*; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D001842:Bone and Bones / Q000473:pathology; D018826:CD13 Antigens / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003600:Cytosol / Q000378:metabolism; D004164:Diphosphonates / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008798:Mevalonic Acid / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism
D000970:Antineoplastic Agents; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D004791:Enzyme Inhibitors; C437105:GGTI 286; C071542:cimadronate; D018826:CD13 Antigens; D020827:rap1 GTP-Binding Proteins; D007930:Leucine; D008798:Mevalonic Acid