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ORCID

http://orcid.org/0000-0003-3922-1874

Date of Award

Spring 5-15-2019

Author's School

Graduate School of Arts and Sciences

Author's Department

Chemistry

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

During proliferation, cells are faced with the anabolic burden of replicating their contents. To understand the biology of cancer, which is characterized by rapidly dividing cells, it is essential to define the metabolic requirements of this process. Accordingly, many studies of proliferative metabolism have been conducted by comparing proliferating tumor tissue to non-proliferating healthy tissue. Such comparisons, however, are complicated by confounding variables and may not reflect metabolic adaptions specific to proliferation. As an alternative, the investigations presented herein focus on fibroblast cells whose proliferation can be contact-inhibited by simple experimental manipulation. The contact-inhibition feature of these fibroblasts enables a metabolic comparison of the same cells in the quiescent and proliferative states. We find that proliferating cells preferentially take up exogenous fatty acids instead of synthesizing them de novo. When abundant exogenous fatty acids are available, proliferating cells (including cancer cells) significantly down-regulate glucose consumption rendering them less susceptible to glycolytic inhibition. Surprisingly, we find that these exogenous fatty acids are largely dispensable for energy production. Instead, the anabolic utilization of these fatty acids is essential to maintain mitochondrial structure and functions that are required for cellular proliferation. In contrast to the common assumption that cellular proliferation increases glycolysis at the cost of decreasing oxidative metabolism, we observe that proliferating fibroblasts have significantly higher oxygen consumption and respiratory efficiency compared to the same cells in the quiescent state. Both increases are supported by mitochondrial fusion. The metabolic attributes that we have associated with cellular proliferation may represent therapeutic targets for the treatment of cancer.

Language

English (en)

Chair and Committee

Gary J. Patti

Committee Members

Timothy A. Wencewicz, Robert E. Blankenship, Michael L. Gross, David A. Ford,

Comments

Permanent URL: https://doi.org/10.7936/4nvw-ak14

Available for download on Monday, May 15, 2119

Included in

Biochemistry Commons

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