Role of Polyamine Oxidase (PAOh1/SMO) in Human Breast Cancer
Annual summary rept. 22 Marc 2005-21 Mar 2006
JOHNS HOPKINS UNIV BALTIMORE MD
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The induction of polyamine catabolism and its production of H2O2 have been implicated in the response to specific anti-tumor polyamine analogues. This project evaluates the ability of Bisethylnorspermine BENSpm to induce the polyamine catabolic enzymes in human breast cancer cell lines and examines the role of their induction in the overall response of breast cancer cell lines to BENSpm treatment. To examine the role of the catabolic enzymes in the response of breast cancer cells to the polyamine analogue N1, N11-bisethylnorspermine BENSpm, a stable knockdown siRNA strategy was used. BENSpm differentially induced SSAT and SMOPAOh1 mRNA and activity in several breast cancer cell lines, while no N1-acetylpolyamine oxidase PAO mRNA or activity was detected. BENSpm treatment inhibited cell growth, decreased intracellular polyamine levels, and decreased ODC activity in all cell lines examined. The stable knockdown of either SSAT or SMOPAOh1 reduced the sensitivity of MDA-MB-231 cells to BENSpm while double knockdown MDA-MB-231 cells were almost entirely resistant to the growth inhibitory effects of the analogue. Further, the H2O2 produced through BENSpm-induced polyamine catabolism was found to be derived exclusively from SMOPAOh1 activity and not through PAO activity on acetylated polyamines. These data suggest that SSAT and SMOPAOh1 activities are the major mediators of the cellular response of breast tumor cells to BENSpm and that PAO plays little or no role in this response.
- Anatomy and Physiology
- Medicine and Medical Research
- Polymer Chemistry