Argyrin A Reveals a Critical Role for the Tumor Suppressor Protein p27^kip1 in Mediating Antitumor Activities in Response to Proteasome Inhibition

authored by

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

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.

External Organisation(s)

Hannover Medical School (MHH)
Helmholtz Centre for Infection Research (HZI)
Max Planck Institute for Biophysical Chemistry (Karl Friedrich Bonhoeffer Institute)
University of Bonn

Type

Article

Journal

CANCER CELL

Volume

14

Pages

23-35

No. of pages

13

ISSN

1535-6108

Publication date

08.07.2008

Publication status

Published

Peer reviewed

Yes

ASJC Scopus subject areas

Oncology, Cell Biology, Cancer Research

Sustainable Development Goals

SDG 3 - Good Health and Well-being

Electronic version(s)

https://doi.org/10.1016/j.ccr.2008.05.016 (Access: Open)