Expression of gamma-aminobutyric acid receptor (subtype A) in prostate cancer.
BACKGROUND
In prostate cancer, gamma-aminobutyric acid (GABA) has been previously reported to increase cellular proliferation via the ionotropic GABAa receptor (GABAar) and to promote cellular invasiveness via the metabotropic GABAb receptor.


METHODS
In this study, we have investigated, by immunohistochemistry, GABAar levels in 12 normal human prostate, 13 benign prostatic hyperplasia (BPH) and 148 human prostate cancer specimens. We have also examined the effect of several GABA agonists and antagonists on the in vitro proliferation of four human prostate cancer cell lines: LNCaP, MDA-PCA-2b, DU145 and PC3.


RESULTS
GABAar immunoreactivity was present in the stroma of ~75% of the normal and BPH specimens, and in 95% of the prostate cancer specimens. Also, low to moderate GABAar staining was observed in the acinar epithelium of 50 (33%) prostate cancer specimens. No correlation was observed between GABAar staining and patient age, Gleason Sum or TNM stage. A GABAa agonist isoguvacine, at doses between 5-50 microg/ml (31-310 microM), stimulated the proliferation of all four human prostate cancer cell lines, tested. Baclofen, a GABAb agonist (up to 50 microg/ml, 234 microM) had no effect on growth. Also, at concentrations up to 100 microg/ml, GABA antagonists, bicuculline (223 microM), picrotoxin (166 microM) and saclofen (400 microM), did not have significant growth-inhibitory effects. However, dihydroergotoxine, which binds the GABAar chloride ion-channel, inhibited cellular proliferation (IC(50) 18-38 microM).


CONCLUSIONS
These data indicate frequent expression of GABAar in prostate cancer and support a role for GABAar in the proliferation of prostate cancer cells.
Abdul
Mansoor
M
Department of Biology, Claflin University, Orangeburg, SC 29115, USA.
Mccray
Shawntae D
SD
Hoosein
Naseema M
NM
D001640:Bicuculline / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D004088:Dihydroergotoxine / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D058786:GABA-B Receptor Agonists; D006801:Humans; D007539:Isonicotinic Acids / Q000494:pharmacology; D008297:Male; D010852:Picrotoxin / Q000494:pharmacology; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011470:Prostatic Hyperplasia / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011963:Receptors, GABA-A / Q000378:metabolism*; D018080:Receptors, GABA-B / Q000378:metabolism; D014407:Tumor Cells, Cultured
D001640:Bicuculline; D004088:Dihydroergotoxine; D018755:GABA Agonists; D018756:GABA Antagonists; D058785:GABA-A Receptor Agonists; D058786:GABA-B Receptor Agonists; D007539:Isonicotinic Acids; D010852:Picrotoxin; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; C015300:isoguvacine