P2-purinergic receptor agonists inhibit the growth of androgen-independent prostate carcinoma cells.
To develop a new approach to the treatment of advanced, hormone-refractory prostate cancer, the signal transductions regulating the growth of human androgen-independent prostate carcinoma cell lines were studied. Agonist-stimulated Ca2+ mobilization, a critical regulatory event in other secretory cell types, was studied as a means of identifying previously undescribed plasma membrane receptors that may transduce a growth inhibitory signal. In all of the cell lines tested, P2-purinergic receptor agonists, including ATP and certain hydrolysis-resistant adenine nucleotides, induced a rapid, transient increase in cytoplasmic free Ca2+ that was detectable at 50 to 100 nM ATP, was maximal at 100 microM ATP, and was inhibited approximately 50% by chelation of extracellular Ca2+. Within 8 s after addition, ATP stimulated accumulation of the polyphosphatidylinositol products inositol (1, 4, 5) trisphosphate, inositol (1, 3, 4) trisphosphate, and inositol tetrakisphosphate. In addition to stimulating phosphatidylinositol turnover and Ca2+ mobilization, ATP and hydrolysis-resistant ATP analogues induced greater than 90% inhibition of the growth of all lines tested. These data demonstrate that human androgen-independent prostate carcinoma cells express functional P2-purinergic receptors linked to phospholipase C, and that agonists of this receptor are markedly growth inhibitory, suggesting a novel therapeutic approach to this common adult neoplasm.
Fang
W G
WG
Clinical Pharmacology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Pirnia
F
F
Bang
Y J
YJ
Myers
C E
CE
Trepel
J B
JB
D000227:Adenine Nucleotides / Q000494:pharmacology; D000728:Androgens / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D002277:Carcinoma / Q000378:metabolism*; D005069:Evaluation Studies as Topic; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D008297:Male; D010716:Phosphatidylinositols / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011983:Receptors, Purinergic / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000378:metabolism
D000227:Adenine Nucleotides; D000728:Androgens; D015220:Calcium Channels; D007295:Inositol Phosphates; D010716:Phosphatidylinositols; D011983:Receptors, Purinergic; D010738:Type C Phospholipases; D002118:Calcium