12(S)-HETE increases intracellular Ca2+ in lymph-endothelial cells disrupting their barrier function in vitro; stabilization by clinical drugs impairing calcium supply. Issue 1 (28th September 2016)

• Record Type: Journal Article
• Authors: Nguyen, Chi Huu; Brenner, Stefan; Huttary, Nicole; Li, Yuanfang; Atanasov, Atanas Georgiev; Dirsch, Verena M.; Holzner, Silvio; Stadler, Serena; Riha, Juliane; Krieger, Sigurd; Milovanovic, Danijela; Fristiohardy, Adryan; Simonitsch-Klupp, Ingrid; Dolznig, Helmut; Saiko, Philipp; Szekeres, Thomas; Giessrigl, Benedikt; Jäger, Walter; Krupitza, Georg
• Is Part Of: Cancer letters. Volume 380:Issue 1(2016)
• Page Start: 174
• Page End: 183
• Publication Date: 2016-09-28
• Subjects: 12(S)-HETE -- Intracellular Ca2+ -- PLC/IP3 -- MYLK -- MLC2 -- Endothelial integrity disruption; Ser19 serine 19 -- MLC2 myosin light chain 2 -- CCID circular chemorepellent induced defect -- MYLK (nonmuscular) myosin light chain kinase -- IP3 inositol trisphosphate -- DAG diacyl-glycerol -- PLC phospholipase C -- PIP2 phosphatidylinositol 4, 5-bisphosphate or PtdIns(4, 5)P2 -- 12(S)-HETE 12S-hydroxy-5Z, 8Z, 10E, 14Z-eicosatetraenoic acid, "S" stereoisomer -- 12-HETER 12(S)-HETE receptor (syn. GPR31) -- PKC protein kinase C -- NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells -- ALOX arachidonate lipoxygenase -- EC endothelial cell -- LEC lymph-endothelial cell -- RHO Ras homolog gene family -- ROCK Rho-associated protein kinase -- ICAM-1 intercellular adhesion molecule 1; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2016.06.022
• Languages: English
• ISSNs: 0304-3835

Abstract

Highlights: Cancer cell-secreted 12(S)-HETE activates MLC2 of adjacent lymphatic endothelial cells. MLC2 activation causes endothelial disintegration facilitating tumor intravasation. The 12(S)-HETE signal is transduced by PLC, Ca 2+ and MYLK. Approved drugs impairing Ca 2+ supply inhibit MLC2 activity and tumor intravasation. Abstract: Secretion of 12(S)-HETE by breast cancer emboli provokes "circular chemorepellent induced defects" (CCIDs) in the adjacent lymphatic vasculature facilitating their intravasation and lymph node metastasis which determines prognosis. Therefore, elucidating the mechanism of lymph endothelial cell (LEC) wall disintegration may provide cues for anti-metastatic intervention. The role of intracellular free Ca 2+ for CCID formation was investigated in LECs using MCF-7 or MDA-MB231 breast cancer cell spheroids in a three-dimensional cell co-culture model. 12(S)-HETE elevated the Ca 2+ level in LEC by activating PLC/IP3 . Downstream, the Ca 2+ -calmodulin kinase MYLK contributed to the phosphorylation of Ser19-MLC2, LEC contraction and CCID formation. Approved clinical drugs, lidoflazine, ketotifen, epiandrosterone and cyclosporine, which reportedly disturb cellular calcium supply, inhibited 12(S)-HETE-induced Ca 2+ increase, Ser19-MLC2 phosphorylation and CCID formation. This treatment strategy may reduce spreading of breast cancer through lymphatics.