The effects of genetic and luminal risk factors on cyclooxygenase-2 expression in human colon cancer cells

Persistent Link:
http://hdl.handle.net/10150/289786
Title:
The effects of genetic and luminal risk factors on cyclooxygenase-2 expression in human colon cancer cells
Author:
Parker, Michele Taylor
Issue Date:
2002
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:
The process of colon carcinogenesis is dependent upon a variety of genetic mutations and intestinal luminal risk factors. These risk factors cooperate to influence pathophysiological targets directly linked to the carcinogenic process. Cyclooxygenase-2 (COX-2) is one such target, and it is found to be upregulated in 50% of colonic adenomas and 85% of carcinomas. The interaction between genetic mutations and luminal risk factors to affect COX-2 expression was explored in this dissertation work. An activated K-ras oncogene and mutant APC tumor suppressor gene both regulate COX-2 posttranscriptionally. Using colon cancer cells with these genetic alterations, we determined that an activated K-ras stabilizes COX-2 mRNA and works through a PKC-dependent mechanism in a cell line-specific manner. K-ras also affected PTEN expression to potentially suppress cell survival. Wild-type APC downregulated COX-2 protein levels without affecting mRNA. APC interfered with PI-3K-dependent signaling of COX-2, and affected PKC-depending signaling to further modulate COX-2 expression. In addition to genetic alterations, luminal factors obtained from the diet influenced COX-2 expression in these colon cancer cell models. Secondary bile acids like deoxycholic acid (DCA) mediated COX-2 protein stability in addition to its known affects on transcription. DCA's affects on COX-2 protein were partially mediated by APC mutational status and PKC-signaling. Polyamines, another luminal risk factor for colon cancer, regulated COX-2 through the induction of RNA processing by the polyamine-dependent gene, eIF-5A and through a reliance on transport through the cell membrane. The chemopreventive agent, Sulindac, has two metabolites---sulindac sulfone and sulindac sulfide. Previous to this study, little was known about the mechanism of action of the sulfone metabolite. We determined that sulindac sulfone suppressed COX-2 protein levels, thus impinging on this protein's ability to signal downstream genes or to produce prostaglandins. In addition, DFMO, a chemopreventive agent that suppresses polyamine synthesis, significantly induced COX-2 protein levels, predicating the importance of combination chemoprevention to battle COX-2-driven tumorigenesis. The intricate cooperation of genetic mutations and luminal risk factors affecting COX-2 expression and subsequently tumorigenesis, suggest that multiagent interventions may be necessary for successful strategies of 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; Cancer Biology
Degree Grantor:
University of Arizona
Advisor:
Gerner, Eugene W.

Full metadata record

DC FieldValue Language
dc.language.isoen_USen_US
dc.titleThe effects of genetic and luminal risk factors on cyclooxygenase-2 expression in human colon cancer cellsen_US
dc.creatorParker, Michele Tayloren_US
dc.contributor.authorParker, Michele Tayloren_US
dc.date.issued2002en_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.abstractThe process of colon carcinogenesis is dependent upon a variety of genetic mutations and intestinal luminal risk factors. These risk factors cooperate to influence pathophysiological targets directly linked to the carcinogenic process. Cyclooxygenase-2 (COX-2) is one such target, and it is found to be upregulated in 50% of colonic adenomas and 85% of carcinomas. The interaction between genetic mutations and luminal risk factors to affect COX-2 expression was explored in this dissertation work. An activated K-ras oncogene and mutant APC tumor suppressor gene both regulate COX-2 posttranscriptionally. Using colon cancer cells with these genetic alterations, we determined that an activated K-ras stabilizes COX-2 mRNA and works through a PKC-dependent mechanism in a cell line-specific manner. K-ras also affected PTEN expression to potentially suppress cell survival. Wild-type APC downregulated COX-2 protein levels without affecting mRNA. APC interfered with PI-3K-dependent signaling of COX-2, and affected PKC-depending signaling to further modulate COX-2 expression. In addition to genetic alterations, luminal factors obtained from the diet influenced COX-2 expression in these colon cancer cell models. Secondary bile acids like deoxycholic acid (DCA) mediated COX-2 protein stability in addition to its known affects on transcription. DCA's affects on COX-2 protein were partially mediated by APC mutational status and PKC-signaling. Polyamines, another luminal risk factor for colon cancer, regulated COX-2 through the induction of RNA processing by the polyamine-dependent gene, eIF-5A and through a reliance on transport through the cell membrane. The chemopreventive agent, Sulindac, has two metabolites---sulindac sulfone and sulindac sulfide. Previous to this study, little was known about the mechanism of action of the sulfone metabolite. We determined that sulindac sulfone suppressed COX-2 protein levels, thus impinging on this protein's ability to signal downstream genes or to produce prostaglandins. In addition, DFMO, a chemopreventive agent that suppresses polyamine synthesis, significantly induced COX-2 protein levels, predicating the importance of combination chemoprevention to battle COX-2-driven tumorigenesis. The intricate cooperation of genetic mutations and luminal risk factors affecting COX-2 expression and subsequently tumorigenesis, suggest that multiagent interventions may be necessary for successful strategies of 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.disciplineCancer Biologyen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorGerner, Eugene W.en_US
dc.identifier.proquest3050337en_US
dc.identifier.bibrecord.b42728101en_US
All Items in UA Campus Repository are protected by copyright, with all rights reserved, unless otherwise indicated.