12-0-Tetradecanoyl Phorbol-13-Acetate Stimulates Rat Growth Hormone (GH) Release through Different Pathways from that of Human Pancreatic GH-Releasing Factor*

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Abstract
The mechanism(s) of action of 12-O-tetradecanoylphorbol-13-acetate (TPA), [the most potent tumor promoter of the phorbol ester family] on rat (r) GH [growth hormone] release was studied in primary rat pituitary cell cultures. TPA stimulated rGH release (3.2- to 4.1-fold above control value) and rTSH and rLH [luteinizing hormone] release (1.4- and 1.7-fold above control values, respectively), but not rPRL [prolactin] release. The ED50 of TPA on rGH secretion was 1.3 .times. 10-9 M compared to 4.5 .times. 10-11 M for human pancreatic GH-releasing factor [hpGRF-(1-44]. If maximally effective doses of TPA or hpGRF-(1-44) were added to the cells, the magnitudes of the increase in rGH release were quite similar for both agents when the incubation period was less than 12 h. When (Bu)2[dibutyl]cAMP was added simultaneously with various doses of TPA, (Bu)2cAMP increased rGH release beyond the maximal effect of TPA. There was an additive effect when hpGRF-(1-44) and TPA were used to stimulate rGH release. Apparently, TPA enhances rGH release through a different pathway than hpGRF-(1-44). TPA failed to increase the formation of intra- and extracellular cAMP; hpGRF-(1-44) increased both, suggesting that TPA stimulates rGH release through an cAMP-independent pathway(s). Protein kinase C was postulated to be a receptor for TPA in human platelets. When phospholipase C, which activates protein kinase C via the formation of diacylglycerol, was added to the cells, rGH release was stimulated in a dose-dependent manner. This effect was not blocked by indomethacin. Evidently, activation of protein kinase C leads to rGH release. The observations are consistent with the hypothesis that TPA activates protein kinase C and causes the release of rGH in normal pituitary cells in culture. Apparently, the mechanism(s) of action of TPA on rGH release is different from that of hpGRF-(1-44).