12(S)-HETE increases intracellular Ca(2+) in lymph-endothelial cells disrupting their barrier function in vitro; stabilization by clinical drugs impairing calcium supply

Huu Chi Nguyen; Stefan Brenner; Nicole Huttary; Yuanfang Li; Atanas Georgiev Atanasov; Verena M Dirsch; Silvio Holzner; Serena Stadler; Juliane Riha; Sigurd Krieger; Danijela Milovanovic; Adryan Fristiohardy; Ingrid Simonitsch-Klupp; Helmut Dolznig; Philipp Saiko; Thomas Szekeres; Benedikt Giessrigl; Walter Jäger; Georg Krupitza

doi:10.1016/j.canlet.2016.06.022

12(S)-HETE increases intracellular Ca(2+) in lymph-endothelial cells disrupting their barrier function in vitro; stabilization by clinical drugs impairing calcium supply

Huu Chi Nguyen
, Stefan Brenner
, Nicole Huttary
, Yuanfang Li
, Atanas Georgiev Atanasov
, Verena M Dirsch
, Silvio Holzner
, Serena Stadler
, Juliane Riha
, Sigurd Krieger
, Danijela Milovanovic
, Adryan Fristiohardy
, Ingrid Simonitsch-Klupp
, Helmut Dolznig
, Philipp Saiko
, Thomas Szekeres
, Benedikt Giessrigl
, Walter Jäger
, Georg Krupitza (Corresponding author)

Publications: Contribution to journal › Article › Peer Reviewed

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.

Original language	English
Pages (from-to)	174-183
Number of pages	10
Journal	Cancer Letters
Volume	380
Issue number	1
DOIs	https://doi.org/10.1016/j.canlet.2016.06.022
Publication status	Published - 28 Sept 2016

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Austrian Fields of Science 2012

106002 Biochemistry
301207 Pharmaceutical chemistry
301204 Pharmacognosy
301212 Clinical pharmacy

Keywords

12(S)-HETE
12-HYDROXYEICOSATETRAENOIC ACID
ANGIOTENSIN-II
BREAST-CANCER SPHEROIDS
CAMP PRODUCTION
Endothelial integrity disruption
FACTOR-KAPPA-B
HUMAN NEUTROPHILS
Intracellular Ca2+
LIGHT-CHAIN KINASE
MLC2
MYLK
PKC-BETA
PLC/IP3
SIGNALING PATHWAY
VESSEL ENDOTHELIUM
Intracellular Ca
PLC/IP

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10.1016/j.canlet.2016.06.022

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Nguyen, H. C., Brenner, S., Huttary, N., Li, Y., Atanasov, A. G., Dirsch, V. M., Holzner, S., Stadler, S., Riha, J., Krieger, S., Milovanovic, D., Fristiohardy, A., Simonitsch-Klupp, I., Dolznig, H., Saiko, P., Szekeres, T., Giessrigl, B., Jäger, W., & Krupitza, G. (2016). 12(S)-HETE increases intracellular Ca(2+) in lymph-endothelial cells disrupting their barrier function in vitro; stabilization by clinical drugs impairing calcium supply. Cancer Letters, 380(1), 174-183. https://doi.org/10.1016/j.canlet.2016.06.022

@article{9609e0b978d045688494e5caaf09b38a,

title = "12(S)-HETE increases intracellular Ca(2+) in lymph-endothelial cells disrupting their barrier function in vitro; stabilization by clinical drugs impairing calcium supply",

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.",

keywords = "12(S)-HETE, 12-HYDROXYEICOSATETRAENOIC ACID, ANGIOTENSIN-II, BREAST-CANCER SPHEROIDS, CAMP PRODUCTION, Endothelial integrity disruption, FACTOR-KAPPA-B, HUMAN NEUTROPHILS, Intracellular Ca2+, LIGHT-CHAIN KINASE, MLC2, MYLK, PKC-BETA, PLC/IP3, SIGNALING PATHWAY, VESSEL ENDOTHELIUM, Intracellular Ca, PLC/IP",

author = "Nguyen, \{Huu Chi\} and Stefan Brenner and Nicole Huttary and Yuanfang Li and Atanasov, \{Atanas Georgiev\} and Dirsch, \{Verena M\} and Silvio Holzner and Serena Stadler and Juliane Riha and Sigurd Krieger and Danijela Milovanovic and Adryan Fristiohardy and Ingrid Simonitsch-Klupp and Helmut Dolznig and Philipp Saiko and Thomas Szekeres and Benedikt Giessrigl and Walter J{\"a}ger and Georg Krupitza",

note = "Publisher Copyright: {\textcopyright} 2016 Elsevier Ireland Ltd",

year = "2016",

month = sep,

day = "28",

doi = "10.1016/j.canlet.2016.06.022",

language = "English",

volume = "380",

pages = "174--183",

journal = "Cancer Letters",

issn = "0304-3835",

publisher = "ELSEVIER IRELAND LTD",

number = "1",

}

Nguyen, HC, Brenner, S, Huttary, N, Li, Y, Atanasov, AG, Dirsch, VM, Holzner, S, Stadler, S, Riha, J, Krieger, S, Milovanovic, D, Fristiohardy, A, Simonitsch-Klupp, I, Dolznig, H, Saiko, P, Szekeres, T, Giessrigl, B, Jäger, W & Krupitza, G 2016, '12(S)-HETE increases intracellular Ca(2+) in lymph-endothelial cells disrupting their barrier function in vitro; stabilization by clinical drugs impairing calcium supply', Cancer Letters, vol. 380, no. 1, pp. 174-183. https://doi.org/10.1016/j.canlet.2016.06.022

TY - JOUR

T1 - 12(S)-HETE increases intracellular Ca(2+) in lymph-endothelial cells disrupting their barrier function in vitro; stabilization by clinical drugs impairing calcium supply

AU - Nguyen, Huu Chi

AU - Brenner, Stefan

AU - Huttary, Nicole

AU - Li, Yuanfang

AU - Atanasov, Atanas Georgiev

AU - Dirsch, Verena M

AU - Holzner, Silvio

AU - Stadler, Serena

AU - Riha, Juliane

AU - Krieger, Sigurd

AU - Milovanovic, Danijela

AU - Fristiohardy, Adryan

AU - Simonitsch-Klupp, Ingrid

AU - Dolznig, Helmut

AU - Saiko, Philipp

AU - Szekeres, Thomas

AU - Giessrigl, Benedikt

AU - Jäger, Walter

AU - Krupitza, Georg

PY - 2016/9/28

Y1 - 2016/9/28

N2 - 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.

AB - 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.

KW - 12(S)-HETE

KW - 12-HYDROXYEICOSATETRAENOIC ACID

KW - ANGIOTENSIN-II

KW - BREAST-CANCER SPHEROIDS

KW - CAMP PRODUCTION

KW - Endothelial integrity disruption

KW - FACTOR-KAPPA-B

KW - HUMAN NEUTROPHILS

KW - Intracellular Ca2+

KW - LIGHT-CHAIN KINASE

KW - MLC2

KW - MYLK

KW - PKC-BETA

KW - PLC/IP3

KW - SIGNALING PATHWAY

KW - VESSEL ENDOTHELIUM

KW - Intracellular Ca

KW - PLC/IP

UR - https://www.scopus.com/pages/publications/84979017423

U2 - 10.1016/j.canlet.2016.06.022

DO - 10.1016/j.canlet.2016.06.022

M3 - Article

C2 - 27390016

SN - 0304-3835

VL - 380

SP - 174

EP - 183

JO - Cancer Letters

JF - Cancer Letters

IS - 1

ER -

12(S)-HETE increases intracellular Ca(2+) in lymph-endothelial cells disrupting their barrier function in vitro; stabilization by clinical drugs impairing calcium supply

Abstract

UN SDGs

Austrian Fields of Science 2012

Keywords

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