Regulation and function of spermidine/spermine N¹ acetyl transferase (SSAT) in colon carcinogenesis

Persistent Link:
http://hdl.handle.net/10150/289966
Title:
Regulation and function of spermidine/spermine N¹ acetyl transferase (SSAT) in colon carcinogenesis
Author:
Babbar, Naveen
Issue Date:
2003
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Epidemiological data suggest that non-steroidal anti-inflammatory drugs (NSAIDs) have anti-tumorigenic activities against colorectal cancer. NSAIDs work by inhibiting cyclooxygenases (COX) enzyme. Sulindac, a NSAID prodrug, is metabolized into pharmacologically active sulfide and sulfone derivatives. Microarray analysis was used to detect COX independent effects of sulindac on gene expression in human colorectal cells. Spermidine/spermine N 1-acetyl transferase (SSAT) gene, which encodes a polyamine catabolic enzyme, was one of the genes induced by clinically relevant sulindac sulfone concentrations. Promoter analysis and mutational studies were done to map the sulindac sulfone dependent response sequences in SSAT 5' flanking sequences, which led to the identification of two Peroxisome Proliferator Activated Receptors (PPARs) response elements (PPREs) in the SSAT gene. PPRE-2 is required for the induction of SSAT by sulindac sulfone and is specifically bound by PPARgamma in the Caco-2 cells, while PPRE-1 is not required for the induction of SSAT by sulindac sulfone, but can be bound by both PPARdelta and PPARgamma. Clinically relevant concentrations of sulfone reduced intracellular polyamine levels, inhibited cell growth and induced apoptosis in colon cancer cells. Further, only sulindac sulfone induced apoptosis could be partially rescued by exogenous polyamines. Upon evaluating other NSAIDs for their action on SSAT gene expression, it was found that they induce SSAT mRNA in either a COX dependent or independent mechanism in colon cancer cells. Studies with physiologically relevant concentrations of aspirin show that these concentrations can induce SSAT expression thereby leading to a decrease in polyamine levels. Activating mutations in K-ras, which is a late process in colon carcinogenesis, led to the suppression of SSAT expression in the Caco-2 cells due to the inhibition of PPARgamma by ERK. K-ras didn't have any effect on the induction of SSAT by sulindac sulfone but partially abolished the apoptosis caused by sulindac sulfone, indicating a possible role of mutant K-ras in sulindac resistant colon polyps. Sulindac sulfone, or Exisulin(TM) have been recently used in clinical trials for the prevention of colon, lung and prostate cancer. The data shown here, suggest that one of the mechanisms, by which sulindac sulfone could act as a chemopreventive agent is to induce the expression of SSAT thereby leading to a decrease in the intracellular polyamines. This reduction in polyamines plays an important part in the apoptosis induced by sulindac sulfone in the colon cancer cells. Further, induction of SSAT seems to a general mechanism for different NSAIDs like aspirin, indomethacin, ibuprofen, sulindac and celecoxib in colon cancer. Aspirin is able to induce SSAT and decrease intracellular polyamines at physiological concentrations, which can lead to a significant reduction in adenoma recurrence. Also, activated K- ras suppressed SSAT, but was not able to abolish the induction of SSAT by sulindac sulfone indicating the potential of using sulindac sulfone in colon cancer chemoprevention.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Biology, Molecular.; Biology, Cell.; Health Sciences, Oncology.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Molecular and Cellular Biology
Degree Grantor:
University of Arizona
Advisor:
Gerner, Eugene W.

Full metadata record

DC FieldValue Language
dc.language.isoen_USen_US
dc.titleRegulation and function of spermidine/spermine N¹ acetyl transferase (SSAT) in colon carcinogenesisen_US
dc.creatorBabbar, Naveenen_US
dc.contributor.authorBabbar, Naveenen_US
dc.date.issued2003en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractEpidemiological data suggest that non-steroidal anti-inflammatory drugs (NSAIDs) have anti-tumorigenic activities against colorectal cancer. NSAIDs work by inhibiting cyclooxygenases (COX) enzyme. Sulindac, a NSAID prodrug, is metabolized into pharmacologically active sulfide and sulfone derivatives. Microarray analysis was used to detect COX independent effects of sulindac on gene expression in human colorectal cells. Spermidine/spermine N 1-acetyl transferase (SSAT) gene, which encodes a polyamine catabolic enzyme, was one of the genes induced by clinically relevant sulindac sulfone concentrations. Promoter analysis and mutational studies were done to map the sulindac sulfone dependent response sequences in SSAT 5' flanking sequences, which led to the identification of two Peroxisome Proliferator Activated Receptors (PPARs) response elements (PPREs) in the SSAT gene. PPRE-2 is required for the induction of SSAT by sulindac sulfone and is specifically bound by PPARgamma in the Caco-2 cells, while PPRE-1 is not required for the induction of SSAT by sulindac sulfone, but can be bound by both PPARdelta and PPARgamma. Clinically relevant concentrations of sulfone reduced intracellular polyamine levels, inhibited cell growth and induced apoptosis in colon cancer cells. Further, only sulindac sulfone induced apoptosis could be partially rescued by exogenous polyamines. Upon evaluating other NSAIDs for their action on SSAT gene expression, it was found that they induce SSAT mRNA in either a COX dependent or independent mechanism in colon cancer cells. Studies with physiologically relevant concentrations of aspirin show that these concentrations can induce SSAT expression thereby leading to a decrease in polyamine levels. Activating mutations in K-ras, which is a late process in colon carcinogenesis, led to the suppression of SSAT expression in the Caco-2 cells due to the inhibition of PPARgamma by ERK. K-ras didn't have any effect on the induction of SSAT by sulindac sulfone but partially abolished the apoptosis caused by sulindac sulfone, indicating a possible role of mutant K-ras in sulindac resistant colon polyps. Sulindac sulfone, or Exisulin(TM) have been recently used in clinical trials for the prevention of colon, lung and prostate cancer. The data shown here, suggest that one of the mechanisms, by which sulindac sulfone could act as a chemopreventive agent is to induce the expression of SSAT thereby leading to a decrease in the intracellular polyamines. This reduction in polyamines plays an important part in the apoptosis induced by sulindac sulfone in the colon cancer cells. Further, induction of SSAT seems to a general mechanism for different NSAIDs like aspirin, indomethacin, ibuprofen, sulindac and celecoxib in colon cancer. Aspirin is able to induce SSAT and decrease intracellular polyamines at physiological concentrations, which can lead to a significant reduction in adenoma recurrence. Also, activated K- ras suppressed SSAT, but was not able to abolish the induction of SSAT by sulindac sulfone indicating the potential of using sulindac sulfone in colon cancer chemoprevention.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectBiology, Molecular.en_US
dc.subjectBiology, Cell.en_US
dc.subjectHealth Sciences, Oncology.en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplineMolecular and Cellular Biologyen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorGerner, Eugene W.en_US
dc.identifier.proquest3108881en_US
dc.identifier.bibrecord.b44824671en_US
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