Diverse roles of 2‐arachidonoylglycerol in invasion of prostate carcinoma cells: Location, hydrolysis and 12‐lipoxygenase metabolism

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Abstract
Endogenous 2‐arachidonoylglycerol (2‐AG) is antiinvasive in androgen‐independent prostate carcinoma (PC‐3) cells. Invasion of PC‐3 cells is also inhibited by exogenously added noladin ether, a non‐hydrolyzable analog of 2‐AG. In contrast, exogenous 2‐AG has the opposite effect. Cell invasion significantly increased with high concentrations of exogenous 2‐AG. In PC‐3 cells, arachidonic acid (AA) and 12‐hydroxyeicosatetraenoic acid (12‐HETE) concentrations increased along with exogenously added 2‐AG, and 12‐HETE concentrations increased with exogenously added AA. Invasion of PC‐3 cells also increased with exogenously added AA and 12(S)‐HETE but not 12(R)‐HETE. The exogenous 2‐AG‐induced invasion of PC‐3 cells was inhibited by 3‐octylthio‐1,1,1‐trifluoropropan‐2‐one (OTFP, an inhibitor of 2‐AG hydrolysis) and baicalein (a 12‐LO inhibitor). Western blot and RT‐PCR analyses indicated expression of 12‐HETE producing lipoxygenases (LOs), platelet‐type 12‐LO (P‐12‐LO) and leukocyte‐type 12‐LO (L‐12‐LO), in PC‐3 cells. These results suggest that exogenous 2‐AG induced, rather inhibited, cell invasion because of its rapid hydrolysis to free AA, and further metabolism by 12‐LO of AA to 12(S)‐HETE, a promoter of PC cell invasion. The results also suggest that PC‐3 cells and human prostate stromal (WPMY‐1) cells released free AA, 2‐AG, and 12‐HETE. In the microenvironment of the PC cells, this may contribute to the cell invasion. The 2‐AG hydrolysis and concentration of 2‐AG in microenvironment are critical for PC cell's fate. Therefore, inhibitors of 2‐AG hydrolysis could potentially serve as therapeutic agents for the treatment of prostate cancer.

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