12(S)-HETE increases the motility of prostate tumor cells through selective activation of PKC_α

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 Ca²⁺-dependent PKC isoform α and and Ca²⁺-independent PKC isoform δ. Pretreatmnent 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 PKCα activator. Our data demonstrate that 12(S)-HETE augments the motility of AT2.1 cells via its selective activation of PKCa which may serve as a key target for the development of anti-metastatic drugs useful for combating prostate cancers.