A Novel EPAC-Specific Inhibitor Suppresses Pancreatic Cancer Cell Migration and Invasion

被引：185

作者：

Almahariq, Muayad ^{[1
]}

Tsalkova, Tamara ^{[1
]}

Mei, Fang C. ^{[1
]}

Chen, Haijun ^{[1
]}

Zhou, Jia ^{[1
]}

Sastry, Sarita K. ^{[3
]}

Schwede, Frank ^{[4
]}

Cheng, Xiaodong ^{[1
,2
]}

机构：

[1] Univ Texas Med Branch, Dept Pharmacol & Toxicol, Galveston, TX 77555 USA

[2] Univ Texas Med Branch, Sealy Ctr Struct Biol & Mol Biophys, Galveston, TX 77555 USA

[3] Univ Texas Med Branch, Dept Biochem & Mol Biol, Galveston, TX 77555 USA

[4] Forschungslab & Biochem Vertrieb GmbH, BIOLOG Life Sci Inst, Bremen, Germany

来源：

MOLECULAR PHARMACOLOGY | 2013年 / 83卷 / 01期

基金：

美国国家卫生研究院;

关键词：

DEPENDENT PROTEIN-KINASE; SELECTIVE CAMP ANALOG; CYCLIC-AMP ANALOG; EXCHANGE FACTOR; BETA-CELLS; REGULATED EXOCYTOSIS; CATALYTIC SUBUNIT; HEPARAN-SULFATE; RAP1; ACTIVATION; I-ALPHA;

D O I：

10.1124/mol.112.080689

中图分类号：

R9 [药学];

学科分类号：

100702 [药剂学];

摘要：

Exchange protein directly activated by cAMP (EPAC) and cAMP-dependent protein kinase (PKA) are two intracellular receptors that mediate the effects of the prototypic second messenger cAMP. Identifying pharmacological probes for selectively modulating EPAC activity represents a significant unmet need within the research field. Herein, we report the identification and characterization of 3-(5-tert-butyl-isoxazol-3-yl)-2-[(3-chlorophenyl)-hydrazono]-3-oxo-propionitrile (ESI-09), a novel non-cyclic nucleotide EPAC antagonist that is capable of specifically blocking intracellular EPAC-mediated Rap1 activation and Akt phosphorylation, as well as EPAC-mediated insulin secretion in pancreatic beta cells. Using this novel EPAC-specific inhibitor, we have probed the functional roles of overexpression of EPAC1 in pancreatic cancer cells. Our studies show that EPAC1 plays an important role in pancreatic cancer cell migration and invasion, and thus represents a potential target for developing novel therapeutic strategies for pancreatic cancer.

引用

页码：122 / 128

页数：7

共 50 条

[1]

The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling [J].

Arnold, K ;

Bordoli, L ;

Kopp, J ;

Schwede, T .

BIOINFORMATICS, 2006, 22 (02) :195-201

[2]

Epac1 promotes melanoma metastasis via modification of heparan sulfate [J].

Baljinnyam, Erdene ;

Umemura, Masanari ;

De Lorenzo, Mariana S. ;

Iwatsubo, Mizuka ;

Chen, Suzie ;

Goydos, James S. ;

Iwatsubo, Kousaku .

PIGMENT CELL & MELANOMA RESEARCH, 2011, 24 (04) :680-687

[3]

Exchange Protein Directly Activated by Cyclic AMP Increases Melanoma Cell Migration by a Ca2+-Dependent Mechanism [J].

Baljinnyam, Erdene ;

De Lorenzo, Mariana S. ;

Xie, Lai-Hua ;

Iwatsubo, Mizuka ;

Chen, Suzie ;

Goydos, James S. ;

Nowycky, Martha C. ;

Iwatsubo, Kousaku .

CANCER RESEARCH, 2010, 70 (13) :5607-5617

[4]

Epac increases melanoma cell migration by a heparan sulfate-related mechanism [J].

Baljinnyam, Erdene ;

Iwatsubo, Kousaku ;

Kurotani, Reiko ;

Wang, Xu ;

Ulucan, Coskun ;

Iwatsubo, Mizuka ;

Lagunoff, David ;

Ishikawa, Yoshihiro .

AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, 2009, 297 (04) :C802-C813

[5]

Adrenaline potentiates insulin-stimulated PKB activation via cAMP and Epac: implications for cross talk between insulin and adrenaline [J].

Brennesvik, EO ;

Ktori, C ;

Ruzzin, J ;

Jebens, E ;

Shepherd, PR ;

Jensen, J .

CELLULAR SIGNALLING, 2005, 17 (12) :1551-1559

[6]

Differential binding of cAMP-dependent protein kinase regulatory subunit isoforms Iα and IIβ to the catalytic subunit [J].

Cheng, XD ;

Phelps, C ;

Taylor, SS .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (06) :4102-4108

[7]

Epac and PKA: a tale of two intracellular cAMP receptors [J].

Cheng, Xiaodong ;

Ji, Zhenyu ;

Tsalkova, Tamara ;

Mei, Fang .

ACTA BIOCHIMICA ET BIOPHYSICA SINICA, 2008, 40 (07) :651-662

[8]

Enhanced Rap1 Activation and Insulin Secretagogue Properties of an Acetoxymethyl Ester of an Epac-selective Cyclic AMP Analog in Rat INS-1 Cells STUDIES WITH 8-pCPT-2′-O-Me-cAMP-AM [J].

Chepurny, Oleg G. ;

Leech, Colin A. ;

Kelley, Grant G. ;

Dzhura, Igor ;

Dzhura, Elvira ;

Li, Xiangquan ;

Rindler, Michael J. ;

Schwede, Frank ;

Genieser, Hans G. ;

Holz, George G. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2009, 284 (16) :10728-10736

[9]

cAMP analog mapping of Epac1 and cAMP kinase - Discriminating analogs demonstrate that Epac and cAMP kinase act synergistically to promote PC-12 cell neurite extension [J].

Christensen, AE ;

Selheim, F ;

de Rooij, J ;

Dremier, S ;

Schwede, F ;

Dao, KK ;

Martinez, A ;

Maenhaut, C ;

Bos, JL ;

Genieser, HG ;

Doskeland, SO .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (37) :35394-35402

[10]

ADENOSINE CYCLIC 3',5'-MONOPHOSPHATE DEPENDENT PROTEIN-KINASE - KINETIC MECHANISM FOR THE BOVINE SKELETAL-MUSCLE CATALYTIC SUBUNIT [J].

COOK, PF ;

NEVILLE, ME ;

VRANA, KE ;

HARTL, FT ;

ROSKOSKI, R .

BIOCHEMISTRY, 1982, 21 (23) :5794-5799

← 1 2 3 4 5 →