12(S)-HETE increases intracellular Ca2+ in lymph-endothelial cells disrupting their barrier function in vitro; stabilization by clinical drugs impairing calcium supply

Autor: Benedikt Giessrigl, Juliane Riha, Georg Krupitza, Silvio Holzner, Verena M. Dirsch, Danijela Milovanovic, Thomas Szekeres, Atanas G. Atanasov, Helmut Dolznig, Philipp Saiko, Yuanfang Li, Adryan Fristiohardy, Walter Jäger, Nicole Huttary, Stefan Brenner, Ingrid Simonitsch-Klupp, Serena Stadler, Sigurd Krieger, Chi Huu Nguyen
Rok vydání: 2016
Předmět:
0301 basic medicine
Cancer Research
Myosin Light Chains
Time Factors
Breast Neoplasms
Inositol 1
4
5-Trisphosphate
Biology
Transfection
Permeability
03 medical and health sciences
0302 clinical medicine
Cell Movement
Spheroids
Cellular
Serine
Humans
12-Hydroxy-5
8
10
14-eicosatetraenoic Acid
Calcium Signaling
Phosphorylation
Myosin-Light-Chain Kinase
Protein kinase C
Calcium Chelating Agents
Lymphatic Vessels
ICAM-1
Dose-Response Relationship
Drug
Kinase
Calcium-Binding Proteins
Intravasation
Endothelial Cells
Calcium Channel Blockers
Coculture Techniques
Cell biology
Endothelial stem cell
030104 developmental biology
Lymphatic system
Oncology
Lymphatic Metastasis
Type C Phospholipases
030220 oncology & carcinogenesis
MCF-7 Cells
Calcium
Female
RNA Interference
Lymph
Cardiac Myosins
Intracellular
Zdroj: Cancer Letters. 380:174-183
ISSN: 0304-3835
DOI: 10.1016/j.canlet.2016.06.022
Popis: 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.
Databáze: OpenAIRE
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