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Loss of inhibitor of apoptosis proteins as a determinant of polyamine analog-induced apoptosis in human melanoma cells

Oncogene volume 22, pages 4964–4972 (2003)Cite this article

Abstract

We have previously shown that the clinically relevant polyamine analog N1,N11-diethylnorspermine (DENSPM) causes rapid apoptosis in human melanoma SK-MEL-28 cells via a series of events that include mitochondrial release of cytochrome c and activation of the caspase cascade. Upstream to these events, DENSPM downregulates polyamine biosynthesis and potently upregulates polyamine catabolism at the level of spermidine/spermine N1-acetyltransferase (SSAT). In searching for downstream effectors that either contribute to or abrogate the apoptotic response, we observed that DENSPM treatment of SK-MEL-28 cells for 30 h led to cytosolic release of Smac/Diablo, a mitochondrial protein known to bind and inhibit the function of inhibitor of apoptosis proteins (IAPs). Subsequently, we found that DENSPM markedly lowered survivin and ML-IAP protein (but not XIAP) levels by 18 h via an apparently Smac/Diablo-independent pathway. Proteasome inhibitors fully prevented survivin and ML-IAP protein loss as well as apoptosis, suggesting that the proteasome-mediated degradation of survivin and ML-IAP is causally linked to the cellular outcome. We also observed that structural analogs of DENSPM which differentially induced SSAT and apoptosis lowered survivin and ML-IAP levels in a manner that correlated with enzyme activity. The linkage between IAPs and SSAT was more directly established by the finding that selective prevention of SSAT induction by small interfering RNA prevented survivin and ML-IAP loss as well as apoptosis during DENSPM treatment. Among the melanoma cell lines (SK-MEL-28, MALME-3M, A375 and LOX), survivin degradation correlated temporally with the onset of DENSPM induced apoptosis or growth inhibition. By contrast, ML-IAP degradation occurred only during rapid apoptosis seen in SK-MEL-28 cells. These data suggest a sequence of events whereby DENSPM induction of SSAT leads to loss of IAP proteins and a more fulminate apoptotic response. The findings implicate survivin and ML-IAP as important determinants of polyamine analog drug action in melanoma cells.

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Abbreviations

DENSPM:

N1,N11-diethylnorspermine also known as DE-333

DE-343:

N1,N12-diethylspermine

DE-443:

3,7,12,17-tetra-azanonadecane [N1,N13-diethyl(aminopropyl)homospermidine]

DE-444:

N1,N14-diethylhomospermine

IAP:

inhibitor of apoptosis protein

ML-IAP:

melanoma IAP (also known as livin)

siRNA:

small interfering RNA

Spm:

spermine

SSAT:

spermidine/spermine N1-acetyltransferase

siSSAT:

siRNA targeting SSAT

XIAP:

X-chromosome-linked IAP

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Acknowledgements

We gratefully acknowledge the skilled technical assistance of Nicholas D Kisiel and Paula Diegelman and helpful discussions with Slavoljub Vujcic. This work was supported in part by Grant NCI RO1 CA-22153 and Institute Core Grant CA-16056.

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  1. Grace Cancer Drug Center, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, 14263, NY, USA

    Ying Chen, Debora L Kramer, Fengzhi Li & Carl W Porter

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Correspondence to Carl W Porter.

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Chen, Y., Kramer, D., Li, F. et al. Loss of inhibitor of apoptosis proteins as a determinant of polyamine analog-induced apoptosis in human melanoma cells. Oncogene 22, 4964–4972 (2003). https://doi.org/10.1038/sj.onc.1206725

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