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.