Overexpression of cysteinyl LT1 receptor in prostate cancer and CysLT1R antagonist inhibits prostate cancer cell growth through apoptosis.
The metabolism of arachidonic acid by either cyclooxygenase or lipoxygenase is believed to play an important role in carcinogenesis. Leukotriene (LT) D4 is a proinflammmatory mediator derived from arachidonic acid through various enzymatic steps, and 5-lipoxygenase is an important factor in generating LTD4. We investigated LTD4 receptor (cysteinyl LT1 receptor: CysLT1R) expression in prostate cancer (PC), as well as the effects of CysLT1R antagonist on cell proliferation in PC cell lines. CysLT1R expression in PC patients, prostatic intraepithelial neoplasia (PIN), benign prostatic hyperplasia (BPH), and normal prostate (NP) tissues were examined. CysLT1R expression was detected by immunohistochemistry. Effects of CysLT1R antagonist on PC cell growth were examined by MTT assay. Flow cytometry and Hoechst staining were used to determine whether or not the CysLT1R antagonist induces apoptosis. Initially, only slight CysLT1R expression was detected in BPH and NP tissues and marked CysLT1R expression was detected in PIN and PC tissues. CysLT1R expression was higher in high-grade cancer than in low-grade cancer. Furthermore, CysLT1R antagonist caused marked inhibition of PC cells in a concentration- and time-dependent manner through early apoptosis. In conclusion, CysLT1R is induced in PC, and the results suggest that CysLT1R antagonist may mediate potent anti-proliferative effects of PC cells. Thus, the target of CysLT1R may become a new therapy in the treatment of PC.
Matsuyama
Masahide
M
Department of Urology, Osaka City University Hospital, Osaka 545-8585, Japan. matsuyama@msic.med.osaka-cu.ac.jp
Hayama
Takuma
T
Funao
Kiyoaki
K
Kawahito
Yutaka
Y
Sano
Hajime
H
Takemoto
Yoshiaki
Y
Nakatani
Tatsuya
T
Yoshimura
Rikio
R
D000085:Acetates / Q000494:pharmacology*; D000368:Aged; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D003521:Cyclopropanes; D018450:Disease Progression; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008875:Middle Aged; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011470:Prostatic Hyperplasia / Q000378:metabolism / Q000473:pathology; D019048:Prostatic Intraepithelial Neoplasia / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology*; D011804:Quinolines / Q000494:pharmacology*; D018077:Receptors, Leukotriene / Q000378:metabolism*; D013440:Sulfides; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000085:Acetates; D003521:Cyclopropanes; D020024:Leukotriene Antagonists; D008565:Membrane Proteins; D011804:Quinolines; D018077:Receptors, Leukotriene; D013440:Sulfides; C083169:leukotriene D4 receptor; C093875:montelukast