Intracellular Ca2+ mediates lipoxygenase-induced proliferation of U-373 MG human astrocytoma cells.
The role of intracellular Ca2+ in the regulation of tumor cell proliferation by products of arachidonic acid (AA) metabolism was investigated using U-373 MG human astrocytoma cells. Treatment with nordihydroguaiaretic acid (NDGA), a lipoxygenase (LOX) inhibitor, or caffeic acid (CA), a specific 5-LOX inhibitor, suppressed proliferation of the tumor cells in a dose-dependent manner. However, indomethacin (Indo), a cyclooxygenase (COX) inhibitor, did not significantly alter proliferation of the tumor cells. At anti-proliferative concentrations, NDGA and CA significantly inhibited intracellular Ca2+ release induced by carbachol, a known intracellular Ca2+ agonist in the tumor cells. Exogenous administration of leukotriene B4 (LTB4), an AA metabolite of LOX pathway, enhanced proliferation of the tumor cells in a concentration-dependent fashion. In addition, LTB4 induced intracellular Ca2+ release. Intracellular Ca2+ inhibitors, such as an intracellular Ca2+ chelator (BAPTA) and intracellular Ca(2+)-release inhibitors (dantrolene and TMB-8), significantly blocked the LTB4-induced enhancement of cell proliferation and intracellular Ca2+ release. These results suggest that LOX activity may be critical for cell proliferation of the human astrocytoma cells and that intracellular Ca2+ may play a major role in the mechanism of action of LOX.
Kim
J A
JA
College of Pharmacy, Yeungnam University, Kyongsan, Korea.
Chung
Y J
YJ
Lee
Y S
YS
D016718:Arachidonic Acid / Q000378:metabolism; D001254:Astrocytoma / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism*; D002118:Calcium / Q000032:analysis / Q000502:physiology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D017136:Ion Transport / Q000187:drug effects / Q000502:physiology; D007975:Leukotriene B4 / Q000494:pharmacology; D008084:Lipoxygenase / Q000502:physiology*; D014407:Tumor Cells, Cultured
D002121:Calcium Channel Blockers; D007975:Leukotriene B4; D016718:Arachidonic Acid; D008084:Lipoxygenase; D002118:Calcium