Argyrin a reveals a critical role for the tumor suppressor protein p27(kip1) in mediating antitumor activities in response to proteasome inhibition.
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).
Nickeleit
Irina
I
Institute for Molecular Biology, Hannover Medical School, 30625 Hannover, Germany.
Zender
Steffen
S
Sasse
Florenz
F
Geffers
Robert
R
Brandes
Gudrun
G
Sörensen
Inga
I
Steinmetz
Heinrich
H
Kubicka
Stefan
S
Carlomagno
Teresa
T
Menche
Dirk
D
Gütgemann
Ines
I
Buer
Jan
J
Gossler
Achim
A
Manns
Michael P
MP
Kalesse
Markus
M
Frank
Ronald
R
Malek
Nisar P
NP
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001808:Blood Vessels / Q000187:drug effects / Q000473:pathology; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009336:Necrosis; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000517:prevention & control; D010456:Peptides, Cyclic / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D061988:Proteasome Inhibitors; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D011719:Pyrazines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D001897:Boronic Acids; C436291:CDKN1B protein, human; D015853:Cysteine Proteinase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D010456:Peptides, Cyclic; D061988:Proteasome Inhibitors; D011719:Pyrazines; D034741:RNA, Small Interfering; C530877:argyrin A; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex