Argyrin A reveals a critical role for the tumor suppressor protein p27kip1 in mediating antitumor activities in response to proteasome inhibition

被引：140

作者：

Nickeleit, Irina ^{[1
]}

Zender, Steffen ^{[1
]}

Sasse, Florenz ^{[4
]}

Geffers, Robert ^{[5
]}

Brandes, Gudrun ^{[2
]}

Soerensen, Inga ^{[1
]}

Steinmetz, Heinrich ^{[6
]}

Kubicka, Stefan ^{[3
]}

Carlomagno, Teresa ^{[8
]}

Menche, Dirk ^{[7
]}

Guetgemann, Ines ^{[9
]}

Buer, Jan ^{[5
]}

Gossler, Achim ^{[1
]}

Manns, Michael P. ^{[3
]}

Kalesse, Markus ^{[7
]}

Frank, Ronald ^{[4
]}

Malek, Nisar P. ^{[1
,3
]}

机构：

[1] Hannover Med Sch, Inst Mol Biol, D-30625 Hannover, Germany

[2] Hannover Med Sch, Inst Cell Biol, D-30625 Hannover, Germany

[3] Hannover Med Sch, Dept Gastroenterol Hepatol & Endocrinol, D-30625 Hannover, Germany

[4] Helmholtz Ctr Infect Res, Dept Biol Chem, D-38124 Braunschweig, Germany

[5] Helmholtz Ctr Infect Res, Dept Cell Biol, D-38124 Braunschweig, Germany

[6] Helmholtz Ctr Infect Res, Res Grp Microbial Drugs, D-38124 Braunschweig, Germany

[7] Helmholtz Ctr Infect Res, Dept Med Chem, D-38124 Braunschweig, Germany

[8] Max Planck Inst Biophys Chem, Dept NMR Based Struct Biol, D-37077 Gottingen, Germany

[9] Univ Bonn, Dept Pathol, D-53127 Bonn, Germany

来源：

CANCER CELL | 2008年 / 14卷 / 01期

关键词：

D O I：

10.1016/j.ccr.2008.05.016

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

A reduction in the cellular levels of the cyclin kinase inhibitor p27(kip1) is frequently found in many human cancers and correlates directly with patient prognosis. In this work, we identify argyrin A, a cyclical peptide derived from the myxobacterium Archangium gephyra, as a potent antitumoral drug. All antitumoral activities of argyrin A depend on the prevention of p27(kip1) destruction, as loss of p27(kip1) expression confers resistance to this compound. We find that argyrin A exerts its effects through a potent inhibition of the proteasome. By comparing the cellular responses exerted by argyrin A with siRNA-mediated knockdown of proteasomal subunits, we find that the biological effects of proteasome inhibition per se depend on the expression of p27(kip1).

引用

页码：23 / 35

页数：13

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