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J. Biol. Chem., Vol. 280, Issue 48, 39843-39851, December 2, 2005

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Spermine Oxidase SMO(PAOh1), Not N¹-Acetylpolyamine Oxidase PAO, Is the Primary Source of Cytotoxic H₂O₂ in Polyamine Analogue-treated Human Breast Cancer Cell Lines^*

Allison Pledgie, Yi Huang, Amy Hacker, Zhe Zhang, Patrick M. Woster, Nancy E. Davidson1, and Robert A. Casero, Jr.2

From the Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, Maryland 21231 and the Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, Wayne State University, Detroit, Michigan 48202

The induction of polyamine catabolism and its production of H₂O₂ have been implicated in the response to specific antitumor polyamine analogues. The original hypothesis was that analogue induction of the rate-limiting spermidine/spermine N¹-acetyltransferase (SSAT) provided substrate for the peroxisomal acetylpolyamine oxidase (PAO), resulting in a decrease in polyamine pools through catabolism, oxidation, and excretion of acetylated polyamines and the production of toxic aldehydes and H₂O₂. However, the recent discovery of the inducible spermine oxidase SMO(PAOh1) suggested the possibility that the original hypothesis may be incomplete. To examine the role of the catabolic enzymes in the response of breast cancer cells to the polyamine analogue N¹,N¹-bis(ethyl)norspermine (BENSpm), a stable knockdown small interfering RNA strategy was used. BENSpm differentially induced SSAT and SMO(PAOh1) mRNA and activity in several breast cancer cell lines, whereas no N¹-acetylpolyamine oxidase PAO mRNA or activity was detected. BENSpm treatment inhibited cell growth, decreased intracellular polyamine levels, and decreased ornithine decarboxylase activity in all cell lines examined. The stable knockdown of either SSAT or SMO(PAOh1) reduced the sensitivity of MDA-MB-231 cells to BENSpm, whereas double knockdown MDA-MB-231 cells were almost entirely resistant to the growth inhibitory effects of the analogue. Furthermore, the H₂O₂ produced through BENSpm-induced polyamine catabolism was found to be derived exclusively from SMO(PAOh1) activity and not through PAO activity on acetylated polyamines. These data suggested that SSAT and SMO(PAOh1) 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.

Received for publication, July 26, 2005 , and in revised form, September 29, 2005.

^* This work was supported by grants from the National Institutes of Health and the Department of Defense. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, 1650 Orleans St., CRB 409, Baltimore, MD 21231. Tel.: 410-955-8489; Fax: 410-614-4073; E-mail: davidna{at}jhmi.edu. ² To whom correspondence may be addressed: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, 1650 Orleans St., CRB 551, Baltimore, MD 21231. Tel.: 410-955-8580; Fax: 410-614-9884; E-mail: rcasero{at}jhmi.edu.

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