阿吉瑞菌素a揭示了肿瘤抑制蛋白p27（kip1）在介导蛋白酶体抑制反应中的抗肿瘤活性方面的关键作用。

Argyrin a reveals a critical role for the tumor suppressor protein p27(kip1) in mediating antitumor activities in response to proteasome inhibition.

作者信息

Nickeleit Irina, Zender Steffen, Sasse Florenz, Geffers Robert, Brandes Gudrun, Sörensen Inga, Steinmetz Heinrich, Kubicka Stefan, Carlomagno Teresa, Menche Dirk, Gütgemann Ines, Buer Jan, Gossler Achim, Manns Michael P, Kalesse Markus, Frank Ronald, Malek Nisar P

机构信息

Institute for Molecular Biology, Hannover Medical School, 30625 Hannover, Germany.

出版信息

Cancer Cell. 2008 Jul 8;14(1):23-35. doi: 10.1016/j.ccr.2008.05.016.

DOI:10.1016/j.ccr.2008.05.016

PMID:18598941

Abstract

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).

摘要

细胞周期蛋白激酶抑制剂p27（kip1）的细胞水平降低在许多人类癌症中经常出现，并且与患者预后直接相关。在这项研究中，我们鉴定出源自粘细菌Geophyra archangium的环肽阿吉林A作为一种有效的抗肿瘤药物。阿吉林A的所有抗肿瘤活性都依赖于对p27（kip1）降解的预防，因为p27（kip1）表达缺失会导致对该化合物产生抗性。我们发现阿吉林A通过有效抑制蛋白酶体发挥作用。通过比较阿吉林A与蛋白酶体亚基的siRNA介导的敲低所产生的细胞反应，我们发现蛋白酶体抑制本身的生物学效应取决于p27（kip1）的表达。