Nuclear localization of Survivin renders HeLa tumor cells more sensitive to apoptosis by induction of p53 and Bax.
Clinical studies have shown that nuclear expression of the inhibitor of apoptosis protein Survivin in tumor cells predicted a favorable prognosis whereas cytosolic-localized protein caused a decreased overall survival. Therefore Survivin's subcellular localization may be important for its anti-apoptotic capacity. To address this question, we investigated localization and function of Survivin in normal human lung fibroblasts (NHLFs) and HeLa tumor cells. NHLFs of early passages expressed Survivin in the nucleus and were highly sensitive to C2 ceramide, which induces the mitochondrial apoptotic pathway. In contrast, NHLFs at higher passages relocated Survivin to the cytosol and became more resistant to C2 ceramide. Blocking nuclear export of Survivin by leptomycin B in HeLa cells increased susceptibility to C2 ceramide. In addition, transduction of HeLa cells with Survivin fused to a nuclear localization signal augmented basal expression levels of p53 and Bax and enhanced sensitivity for intrinsic apoptosis. Those findings suggest that a predominant nuclear localization of Survivin increases the sensitivity for pro-apoptotic stimuli, whereas nuclear export enables Survivin to fulfill its inhibitor of apoptosis function. A therapeutic intervention which holds Survivin in the nucleus of tumor cells might improve cancer therapy.
Temme
Achim
A
Institute of Immunology, Medical Faculty Carl Gustav Carus, Technical University Dresden, Fetscherstrasse 74, 01307 Dresden, Germany. temme@rcs.urz.tu-dresden.de
Rodriguez
Jose A
JA
Hendruschk
Sandy
S
Günes
Serap
S
Weigle
Bernd
B
Schäkel
Knut
K
Schmitz
Marc
M
Bachmann
Michael
M
Schackert
Gabriele
G
Rieber
E Peter
EP
D017209:Apoptosis; D001483:Base Sequence; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D017931:DNA Primers; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008168:Lung / Q000166:cytology / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism; D000077022:Survivin; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis*
C107489:BIRC5 protein, human; D017931:DNA Primers; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein