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J. Biol. Chem., Vol. 278, Issue 48, 47762-47775, November 28, 2003
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Cyclooxygenase-independent Induction of Apoptosis by Sulindac Sulfone Is Mediated by Polyamines in Colon Cancer*
¶¶**
From the
Arizona Cancer Center, the Biochemistry, Molecular and Cellular Biology Graduate Program, and the ¶Department of Cell Biology and Anatomy, The University of Arizona, Tucson, Arizona 85724 and ||The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231
Sulindac, a non-steroidal anti-inflammatory prodrug, is metabolized into pharmacologically active sulfide and sulfone derivatives. Sulindac sulfide, but not sulindac sulfone, inhibits cyclooxygenase (COX) enzyme activities, yet both derivatives have growth inhibitory effects on colon cancer cells. Microarray analysis was used to detect COX-independent effects of sulindac on gene expression in human colorectal cells. Spermidine/sperm-ine N1-acetyltransferase (SSAT) gene, which encodes a polyamine catabolic enzyme, was induced by clinically relevant sulindac sulfone concentrations. Northern blots confirmed increased SSAT RNA levels in these colon cancer cells. Deletion analysis and mutational studies were done to map the sulindac sulfone-dependent response sequences in the SSAT 5'-flanking sequences. This led us to the identification of two peroxisome proliferator-activated receptor (PPAR) response elements (PPREs) in the SSAT gene. PPRE-2, at +48 bases relative to the transcription start site, is required for the induction of SSAT by sulindac sulfone and is specifically bound by PPAR
in the Caco-2 cells as shown by transfection and gel shift experiments. PPRE-1, at–323 bases relative to the start site, is not required for the induction of SSAT by sulindac sulfone but can be bound by both PPAR
and PPAR. Sulindac sulfone reduced cellular polyamine contents in the absence but not in the presence of verapamil, an inhibitor of the export of monoacetyl diamines, inhibited cell proliferation and induced apoptosis. The induced apoptosis could be partially rescued by exogenous putrescine. These data suggest that apoptosis induced by sulindac sulfone is mediated, in part, by the COX-independent, PPAR-dependent transcriptional activation of SSAT, leading to reduced tissue polyamine contents in human colon cancer cells.
Received for publication, July 7, 2003 , and in revised form, September 9, 2003.
* This work was supported by National Institutes of Health Grants CA23074, CA72008, CA51085, and CA95060 and Arizona Disease Control Research Commission (ADCRC) Contract No. 1516. 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.
** To whom correspondence should be addressed: Arizona Cancer Center, 1515 N. Campbell Ave., P. O. Box 245024, Tucson, AZ 85724. Tel.: 520-626-2197; Fax: 520-626-4480; E-mail: egerner{at}azcc.arizona.edu.
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