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ucin1321888795.pdf (2.35 MB)
ETD Abstract Container
Abstract Header
An Oncogenic Signal Pathway Dictates the Metabolic Requirements for Survival
Author Info
Barger, Jennifer F.
Permalink:
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1321888795
Abstract Details
Year and Degree
2011, PhD, University of Cincinnati, Medicine: Cell and Molecular Biology.
Abstract
The specific oncogenic events driving a particular tumor shape the way tumors respond to therapeutic regimens. Recent observations reveal that biosynthetic and bioenergetic benefits derived from oncogenic mutations activate glycolysis, glutaminolysis and fatty acid metabolism. Activation of each metabolic program imparts metabolic requirements for survival, and provides the rational for a chemotherapeutic strategy that targets the oncogene-directed signaling pathways responsible for the metabolic reprogramming. The Akt signal transduction pathway drives glycolysis and is the most frequently activated pathway in human cancer. Interruption of glucose metabolism in cells with activated Akt is cytotoxic, implying that oncogenic activation of Akt renders cells ‘addicted’ to glucose. Thus, disrupting Akt-dependent signal transduction could deprive the tumor cell of the signals necessary to sustain glycolysis, resulting in apoptosis. We took two separate approaches to investigate the therapeutic potential of targeting Akt-driven metabolism in cancer. We identified several compounds from a pharmaceutical grade library that are specifically cytotoxic for Akt-expressing cells, while preserving Bcl-xL-dependent survival. Further, these compounds enhanced the cytotoxicity of the chemotherapeutic rapamycin and decreased the activation of Akt. In the second approach, we investigated the potential of S6K1 to serve as a target for counteracting the glucose-dependent survival induced by the BCR-ABL oncogene, which drives chronic myelogenous leukemia. S6K1 inactivation suppressed glycolysis, but did not induce apoptosis. Instead, S6K1 inactivation triggered compensatory fatty acid oxidation capable of supporting glucose-independent cell survival. Further, S6K1 inactivation sensitized cells to inhibition of fatty acid oxidation. These data reveal that metabolic compensation is an important determinant of the cytotoxic response to targeted therapeutics. Combined inactivation of fatty acid oxidation with agents that target critical signaling pathways is an important new opportunity for developing cancer therapeutics.
Committee
David Plas, PhD (Committee Chair)
Leighton Grimes, PhD (Committee Member)
Robert Brackenbury, PhD (Committee Member)
David D'Alessio, MD (Committee Member)
Maria Diaz-Meco, PhD (Committee Member)
Shao-Chun Wang, PhD (Committee Member)
Matthew Wortman, PhD (Committee Member)
Pages
174 p.
Subject Headings
Cellular Biology
Keywords
glycolysis
;
fatty acid oxidation
;
BCR-ABL
;
metabolism
;
cancer
;
cancer therapeutics
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Citations
Barger, J. F. (2011).
An Oncogenic Signal Pathway Dictates the Metabolic Requirements for Survival
[Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1321888795
APA Style (7th edition)
Barger, Jennifer.
An Oncogenic Signal Pathway Dictates the Metabolic Requirements for Survival.
2011. University of Cincinnati, Doctoral dissertation.
OhioLINK Electronic Theses and Dissertations Center
, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1321888795.
MLA Style (8th edition)
Barger, Jennifer. "An Oncogenic Signal Pathway Dictates the Metabolic Requirements for Survival." Doctoral dissertation, University of Cincinnati, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1321888795
Chicago Manual of Style (17th edition)
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Document number:
ucin1321888795
Download Count:
443
Copyright Info
© 2011, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.