12(S)-HETE increases the motility of prostate tumor cells through selective activation of PKC alpha.
Prostate carcinoma has become the second most fatal cancer in American men. In rat Dunning prostate adenocarcinoma cells, increased cellular motility has been associated positively with their increased metastatic potential. However, the mechanism(s) responsible for regulation of tumor cell motility is poorly understood. We have reported that a lipoxygenase metabolite of arachidonic acid 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE] augments tumor cell metastatic potential through activation of protein kinase C (PKC). We report here that 12(S)-HETE increased the motility of AT2.1 cells and this 12(S)-HETE increased motility was inhibited by PKC inhibitor calphostin C. Western blot analysis revealed that AT2.1 cells expressed the Ca(2+)-dependent PKC isoform alpha and Ca(2+)-independent PKC isoform delta. Pretreatment of cells with a Ca2+ chelator BAPTA blocked the 12(S)-HETE increased motility. Further, the motility of AT2.1 cells was increased in a dose dependent manner by thymelea toxin, a selective PKC alpha activator. Our data demonstrate that 12(S)-HETE augments the motility of AT2.1 cells via its selective activation of PKC alpha which may serve as a key target for the development of antimetastatic drugs useful for combating prostate cancers.
Liu
B
B
Department of Radiation Oncology, Wayne State University, Detroit, MI 48202, USA.
Maher
R J
RJ
De Jonckheere
J P
JP
Popat
R U
RU
Stojakovic
S
S
Hannun
Y A
YA
Porter
A T
AT
Honn
K V
KV
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000494:pharmacology*; D000230:Adenocarcinoma / Q000201:enzymology / Q000503:physiopathology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis / Q000378:metabolism*; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000503:physiopathology*; D011493:Protein Kinase C / Q000096:biosynthesis / Q000378:metabolism*; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D051381:Rats; D014407:Tumor Cells, Cultured
D002614:Chelating Agents; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D009281:Naphthalenes; D004533:Egtazic Acid; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; C497260:Prkcd protein, rat; C496628:PRKCA protein, human; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; C058819:calphostin C; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium