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

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).
Authors	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
Journal	Cancer cell (Cancer Cell) Vol. 14 Issue 1 Pg. 23-35 (Jul 08 2008) ISSN: 1878-3686 [Electronic] United States
PMID	18598941 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Angiogenesis Inhibitors Boronic Acids CDKN1B protein, human Cysteine Proteinase Inhibitors Intracellular Signaling Peptides and Proteins Peptides, Cyclic Proteasome Inhibitors Pyrazines RNA, Small Interfering argyrin A Cyclin-Dependent Kinase Inhibitor p27 Bortezomib Proteasome Endopeptidase Complex
Topics	Angiogenesis Inhibitors (pharmacology) Animals Apoptosis (drug effects) Blood Vessels (drug effects, pathology) Boronic Acids (pharmacology) Bortezomib Cell Cycle (drug effects) Cell Proliferation (drug effects) Cyclin-Dependent Kinase Inhibitor p27 Cysteine Proteinase Inhibitors (pharmacology) Dose-Response Relationship, Drug HCT116 Cells HeLa Cells Humans Intracellular Signaling Peptides and Proteins (metabolism) Mice Mice, Nude Necrosis Neoplasms (blood supply, drug therapy, enzymology, pathology) Neovascularization, Pathologic (enzymology, prevention & control) Peptides, Cyclic (pharmacology) Proteasome Endopeptidase Complex (genetics, metabolism) Proteasome Inhibitors Protein Processing, Post-Translational (drug effects) Pyrazines (pharmacology) RNA Interference RNA, Small Interfering (metabolism) Time Factors Transfection Up-Regulation Xenograft Model Antitumor Assays

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