Date on Master's Thesis/Doctoral Dissertation

8-2015

Document Type

Master's Thesis

Degree Name

M.S.

Department

Pharmacology and Toxicology

Degree Program

Pharmacology and Toxicology, MS

Committee Chair

Hein, David

Committee Co-Chair (if applicable)

States, J. Christopher

Committee Member

States, J. Christopher

Committee Member

Zhang, Xiang

Committee Member

Klinge, Carolyn

Committee Member

Rai, Shesh

Subject

Cancer--Molecular aspects; Enzymes; Breast--Cancer

Abstract

Human arylamine N-acetyltransferase 1 (NAT1) is a phase II xenobiotic metabolizing enzyme that is found in almost all tissues of the body. Expression of NAT1 is commonly elevated in several cancers including breast cancer. However, the exact mechanism by which NAT1 expression affects cancer risk and progression remains unclear. Three MDA-MB-231 breast adenocarcinoma cell lines that stably express wild-type, increased, and decreased levels of human NAT1 have been constructed and characterized for NAT1 mRNA, NAT1 acetylation activity, cell doubling rates, and endogenous acetyl-CoA levels. Differences in polar metabolic profile between these three cell lines were investigated using a comprehensive GC×GC−TOF MS system. Increased levels of human NAT1 in the transformed cell lines resulted in a statistically significant decreased abundance of the metabolite palmitoleic acid with one-way ANOVA p = 0.0004, when compared to normal and decreased levels of human NAT1. We hypothesize that increased NAT1 activity leads to increased hydrolysis of acetyl-CoA thus leaving less acetyl-CoA available to participate in other reactions. The fatty acid synthesis pathway utilizes acetyl-CoA in the first two reactions of the pathway and eventually leads to the synthesis of palmitoleic acid (16:1). These data suggest a link between increased levels of NAT1 activity and decreased flux of acetyl-CoA through this portion of the fatty acid synthesis pathway.

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