Both 12-hydroxyheptadecatrienoic
acid (12-HHT) and
thromboxane A2 (TXA2) are products derived from
prostaglandin H2 (
PGH2) catalyzed by
thromboxane synthase. Whether or not they exhibit similar actions remains to be determined. While TXA2-induced activation of
extracellular signal-regulated kinases (ERKs) has been extensively studied, 12-HHT-induced activation of ERKs has not been explored. We reported for the first time that
12-HHT induced activation of ERKs in human
prostate cancer cell line, PC3. We also compared the mechanisms of 12-HHT- and
I-BOP-, a TXA2 mimetic, mediated ERK activation in PC3 cells. The activation of ERKs induced by either agent was shown to involve
protein kinase C (PKC)-,
protein kinase A (PKA)-,
Src kinase and phosphoinositide-3
kinase (PI-3K)-dependent mechanisms in addition to the transactivation of the
EGF receptor (EGFR) and the involvement of
matrix metalloproteinases (
MMPs) based on the sensitivity of the activation to their respective inhibitors. JNK/SAPK and
p38 MAPK pathways were responsive to
I-BOP but not to
12-HHT stimulation. Both 12-HHT- and
I-BOP-induced activations of ERKs were also examined in other human
prostate cancer cells, human
lung cancer cells, and human lung fibroblast.
I-BOP appeared to induce activation of ERKs in most cell lines, whereas
12-HHT induced activation of ERKs only in lung fibroblast in addition to PC3 cells. It appears that TPs are more generally expressed and the potential
12-HHT receptor (s) is expressed in limited specific cell types. Our results suggest that increased expression of
thromboxane synthase as seen in prostate
tumor may stimulate
tumorigenesis as a consequence of concurrent increased synthesis of two
fatty acids capable of activating ERKs.