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Makhov P , Golovine K , Uzzo RG , Rothman J , Crispen PL , Shaw T , Scoll BJ , Kolenko VM
Zinc chelation induces rapid depletion of the X-linked inhibitor of apoptosis and sensitizes prostate cancer cells to TRAIL-mediated apoptosis
Cell Death Differ. 2008 Nov;15(11) :1745-51
PMID: 18617897    PMCID: PMC2585550   
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Abstract
The X-linked inhibitor of apoptosis (XIAP), the most potent member of the inhibitor of apoptosis protein (IAP) family of endogenous caspase inhibitors, blocks the initiation and execution phases of the apoptotic cascade. As such, XIAP represents an attractive target for treating apoptosis-resistant forms of cancer. Here, we demonstrate that treatment with the membrane-permeable zinc chelator, N,N,N',N',-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN) induces a rapid depletion of XIAP at the post-translational level in human PC-3 prostate cancer cells and several non-prostate cell lines. The depletion of XIAP is selective, as TPEN has no effect on the expression of other zinc-binding members of the IAP family, including cIAP1, cIAP2 and survivin. The downregulation of XIAP in TPEN-treated cells occurs via proteasome- and caspase-independent mechanisms and is completely prevented by the serine protease inhibitor, Pefabloc. Finally, our studies demonstrate that TPEN promotes activation of caspases-3 and -9 and sensitizes PC-3 prostate cancer cells to TRAIL-mediated apoptosis. Taken together, our findings indicate that zinc-chelating agents may be used to sensitize malignant cells to established cytotoxic agents via downregulation of XIAP.
Notes
Makhov, P Golovine, K Uzzo, R G Rothman, J Crispen, P L Shaw, T Scoll, B J Kolenko, V M R01 CA108890/CA/NCI NIH HHS/United States Research Support, N.I.H., Extramural England Cell death and differentiation Cell Death Differ. 2008 Nov;15(11):1745-51. Epub 2008 Jul 11.