P2-purinergic receptor agonists inhibit the growth of androgen-independent prostate carcinoma cells

• Published in: The Journal of clinical investigation Vol. 89; no. 1; pp. 191 - 196
• Main Authors: WEI-GANG FANG, PIRNIA, F, YUNG-JUE BANG, MYERS, C. E, TREPEL, J. B
• Format: Journal Article
• Language: English
• Published: Ann Arbor, MI American Society for Clinical Investigation 1992
• Subjects: Adenine Nucleotides - pharmacology; Androgens - metabolism; Biological and medical sciences; Calcium - metabolism; Calcium Channels - metabolism; Carcinoma - metabolism; Evaluation Studies as Topic; Humans; Inositol Phosphates - metabolism; Male; Medical sciences; Nephrology. Urinary tract diseases; Phosphatidylinositols - metabolism; Prostatic Neoplasms - metabolism; Receptors, Purinergic - metabolism; Signal Transduction - physiology; Tumor Cells, Cultured; Tumors of the urinary system; Type C Phospholipases - metabolism; Urinary tract. Prostate gland; Human; Agonist; Purinergic receptor; Exploration; Malignant tumor; Male genital diseases; Genital diseases
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci115562

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.