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

Michael P. Endsley, Nitin Aggarwal, Marilyn A. Isbell, Craig E. Wheelock, Bruce D. Hammock, John R. Falck, William B. Campbell, Kasem Nithipatikom

Research output: Contribution to journalArticle

43 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)984-991
Number of pages8
JournalInternational Journal of Cancer
Volume121
Issue number5
DOIs
StatePublished - Sep 1 2007

Keywords

  • 12-LO
  • 2-arachidonoylglycerol
  • Cell invasion
  • Hydrolysis
  • Prostate cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Endsley, M. P., Aggarwal, N., Isbell, M. A., Wheelock, C. E., Hammock, B. D., Falck, J. R., Campbell, W. B., & Nithipatikom, K. (2007). Diverse roles of 2-arachidonoylglycerol in invasion of prostate carcinoma cells: Location, hydrolysis and 12-lipoxygenase metabolism. International Journal of Cancer, 121(5), 984-991. https://doi.org/10.1002/ijc.22761