Activation of extracellular signal-regulated kinase by 12-hydroxyheptadecatrienoic acid in prostate cancer PC3 cells.
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.
Li
Xiuling
X
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082, USA.
Wei
Jingyan
J
Tai
Hsin-Hsiung
HH
D001671:Biochemistry / Q000379:methods; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008954:Models, Biological; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D017482:Receptors, Thromboxane / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000378:metabolism
D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D017482:Receptors, Thromboxane; C061750:7-(3-(3-hydroxy-4-(4'-iodophenoxy)-1-butenyl)-7-oxabicyclo(2.2.1)heptan-2-yl)-5-heptenoic acid; C008033:12-hydroxy-5,8,10-heptadecatrienoic acid; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D020782:Matrix Metalloproteinases; D013930:Thromboxane-A Synthase