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A Novel Polyarginine Containing Smac Peptide Conjugate that Mediates Cell Death in Tumor and Healthy Cells

[ Vol. 4 , Issue. 4 ]

Author(s):

S. Heckl, A. Sturzu, M. Regenbogen, A. Beck, G. Feil, A. Gharabaghi and H. Echner   Pages 348 - 354 ( 7 )

Abstract:


The seven N-terminal amino acids AVPIAQK (SmacN7) of the mitochondrial protein Smac (second mitochondria- derived activator of caspase) promote caspase activation by binding specifically to inhibitor of apoptosis proteins (IAPs) and blocking their inhibitory activity. SmacN7 cannot pass through the cell membrane, but to be of therapeutic use it would be essential for it to enter the cell. To achieve transmembrane transport of SmacN7 we coupled it to a novel fluorescein isothiocyanate (FITC)-labelled transmembrane transport peptide RRRRK(FITC)RRRR via β-alanine to produce the conjugate AVPIAQKβA RRRRK(FITC)RRRR. Because IAPs are much more strongly expressed in the cytoplasm of tumor cells, we expected this conjugate to produce staining of the cytoplasm, and for this to be stronger in tumor cells than in healthy cells. Surprisingly, we found strong nuclear uptake of the Smac conjugate and of the transport peptide alone without subsequent release in both tumor cells and healthy cells from the bladder, prostate, and brain. This was accompanied by cell death. In contrast to expectations, it appears that the apoptotic effects observed do not result from the SmacN7 cargo alone.

Keywords:

Smac, polyarginine, cell nucleus, cell death, transmembrane transport, glioma, bladder, prostate

Affiliation:

Department of Neuroradiology,University of Tubingen, Medical School, Hoppe-Seyler-Str. 3, 72076 Tubingen, Germany.



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