PAT-1 mediates the antiangiogenic and profibrinolytic effects of 16K prolactin

被引：81

作者：

Bajou, Khalid ^{[1
]}

Herkenne, Stephanie ^{[1
]}

Thijssen, Victor L. ^{[2
,3
]}

D'Amico, Salvino ^{[1
]}

Ngoc-Quynh-Nhu Nguyen ^{[1
]}

Bouche, Ann ^{[4
,5
]}

Tabruyn, Sebastien ^{[1
]}

Srahna, Mohammed ^{[1
]}

Carabin, Jean-Yves ^{[1
]}

Nivelles, Olivier ^{[1
]}

Paques, Cecile ^{[1
]}

Cornelissen, Ivo ^{[4
,5
]}

Lion, Michelle ^{[1
]}

Noel, Agnes ^{[6
]}

Gils, Ann ^{[7
]}

Vinckier, Stefan ^{[4
,5
]}

Declerck, Paul J. ^{[7
]}

Griffioen, Arjan W. ^{[2
]}

Dewerchin, Mieke ^{[4
,5
]}

Martial, Joseph A. ^{[1
]}

Carmeliet, Peter ^{[4
,5
]}

Struman, Ingrid ^{[1
]}

机构：

[1] Univ Liege, Mol Angiogenesis Lab, Interdisciplinary Cluster Appl Genoprote GIGA Res, Liege, Belgium

[2] Vrije Univ Amsterdam Med Ctr, Dept Med Oncol, Angiogenesis Lab, Amsterdam, Netherlands

[3] Vrije Univ Amsterdam Med Ctr, Dept Radiotherapy, Amsterdam, Netherlands

[4] VIB, Vesalius Res Ctr VRC, Lab Angiogenesis & Neurovasc Link, Leuven, Belgium

[5] Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Neurovasc Link, Leuven, Belgium

[6] Univ Liege, GIGA Res Ctr, Unit Biol Tumor & Dev, Liege, Belgium

[7] Katholieke Univ Leuven, Dept Pharmaceut & Pharmacol Sci, Lab Therapeut & Diagnost Antibodies, Leuven, Belgium

来源：

NATURE MEDICINE | 2014年 / 20卷 / 07期

基金：

欧洲研究理事会;

关键词：

PLASMINOGEN-ACTIVATOR INHIBITOR-1; CAPILLARY ENDOTHELIAL-CELLS; FACTOR-KAPPA-B; TUMOR-GROWTH; UROKINASE RECEPTOR; GENE-TRANSFER; ANGIOGENESIS; PROTEIN; CANCER; PAI-1;

D O I：

10.1038/nm.3552

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The N-terminal fragment of prolactin (16K PRL) inhibits tumor growth by impairing angiogenesis, but the underlying mechanisms are unknown. Here, we found that 16K PRL binds the fibrinolytic inhibitor plasminogen activator inhibitor-1 (PAI-1), which is known to contextually promote tumor angiogenesis and growth. Loss of PAI-1 abrogated the antitumoral and antiangiogenic effects of 16K PRL. PAI-1 bound the ternary complex PAI-1-urokinase-type plasminogen activator (uPA)-uPA receptor (uPAR), thereby exerting antiangiogenic effects. By inhibiting the antifibrinolytic activity of PAI-1, 16K PRL also protected mice against thromboembolism and promoted arterial clot lysis. Thus, by signaling through the PAI-1-uPA-uPAR complex, 16K PRL impairs tumor vascularization and growth and, by inhibiting the antifibrinolytic activity of PAI-1, promotes thrombolysis.

引用

页码：741 / 747

页数：7

共 44 条

[1] The plasminogen activator inhibitor PAI-1 controls in vivo tumor vascularization by interaction with proteases, not vitronectin:: Implications for antiangiogenic strategies [J].

Bajou, K ;

Masson, V ;

Gerard, RD ;

Schmitt, PM ;

Albert, V ;

Praus, M ;

Lund, LR ;

Frandsen, TL ;

Brunner, N ;

Dano, K ;

Fusenig, NE ;

Weidle, U ;

Carmeliet, G ;

Loskutoff, D ;

Collen, D ;

Carmeliet, P ;

Foidart, JM ;

Noël, AS .

JOURNAL OF CELL BIOLOGY, 2001, 152 (04) :777-784

[2] Host-derived plasminogen activator inhibitor-1 (PAI-1) concentration is critical for in vivo tumoral angiogenesis and growth [J].

Bajou, K ;

Maillard, C ;

Jost, M ;

Lijnen, HR ;

Gils, A ;

Declerck, P ;

Carmeliet, P ;

Foidart, JM ;

Noel, A .

ONCOGENE, 2004, 23 (41) :6986-6990

[3] Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization [J].

Bajou, K ;

Noël, A ;

Gerard, RD ;

Masson, V ;

Brunner, N ;

Holst-Hansen, C ;

Skobe, M ;

Fusenig, NE ;

Carmeliet, P ;

Collen, D ;

Foidart, JM .

NATURE MEDICINE, 1998, 4 (08) :923-928

[4]

Bentzien F, 2001, CANCER RES, V61, P7356

[5] uPAR-uPA-PAI-l interactions and signaling: A vascular biologist's view [J].

Binder, Bernd R. ;

Mihaly, Judit ;

Prager, Gerald W. .

THROMBOSIS AND HAEMOSTASIS, 2007, 97 (03) :336-342

[6] UROKINASE AND UROKINASE RECEPTOR - A PARACRINE AUTOCRINE SYSTEM REGULATING CELL-MIGRATION AND INVASIVENESS [J].

BLASI, F .

BIOESSAYS, 1993, 15 (02) :105-111

[7] Inhibitory role of plasminogen activator inhibitor-1 in arterial wound healing and neointima formation - A gene targeting and gene transfer study in mice [J].

Carmeliet, P ;

Moons, L ;

Lijnen, HR ;

Janssens, S ;

Lupu, F ;

Collen, D ;

Gerard, RD .

CIRCULATION, 1997, 96 (09) :3180-3191

[8] Targeting the tumour vasculature: insights from physiological angiogenesis [J].

Chung, Alicia S. ;

Lee, John ;

Ferrara, Napoleone .

NATURE REVIEWS CANCER, 2010, 10 (07) :505-514

[9] A SPECIFIC, HIGH-AFFINITY, SATURABLE BINDING-SITE FOR THE 16-KILODALTON FRAGMENT OF PROLACTIN ON CAPILLARY ENDOTHELIAL-CELLS [J].

CLAPP, C ;

WEINER, RI .

ENDOCRINOLOGY, 1992, 130 (03) :1380-1386

[10] Vasoinhibins:: endogenous regulators of angiogenesis and vascular function [J].

Clapp, Carmen ;

Aranda, Jorge ;

Gonzalez, Carmen ;

Jeziorski, Michael C. ;

de la Escalera, Gonzalo Martinez .

TRENDS IN ENDOCRINOLOGY AND METABOLISM, 2006, 17 (08) :301-307

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