TERRY-DISSERTATION-2022.pdf (8.05 MB)
The Function of CD36 in Tumorigenesis
thesis
posted on 2022-05-01, 00:00 authored by Alexander R TerryDuring matrix detachment, tumor cells grow as multicellular clusters, and metabolism in this setting has been shown to recapitulate early stages of tumorigenesis. We previously found that detached cells activate AMPK to inhibit fatty acid synthesis and induce fatty acid oxidation, which raises the question of how clustered cells maintain the integrity and biogenesis of membrane lipids. Here, we show that CD36, a transmembrane protein implicated in lipid uptake and utilization, is robustly induced in a p38- and AMPK-dependent manner during anchorage independent growth. Preceding the induction of CD36, ER stress is induced which decreases the level of SCD1, an ER-resident protein that produces monounsaturated fatty acids. We found that CD36 promotes selective uptake of monounsaturated fatty acids during matrix detachment, and deletion of CD36 more closely resembles SCD1-deficiency. Specifically, CD36-deletion caused accumulation of saturated fatty acids, which represses fatty acid synthesis through allosteric action on both AMPK and ACC and induces ER stress due to over incorporation of saturated fatty acids into membrane glycerolipids. In a mouse model of breast cancer, we found that systemic deletion of CD36 following tumor onset, which emulates drug therapy, diminished the pro-tumorigenic effect of a high fat diet. Consistent with our in vitro results, tumor lysates from CD36-deficient mice fed a high fat diet showed enhanced activation of AMPK and markers of ER stress. Taken together, our results suggest that CD36 supports tumorigenesis through selective uptake of monounsaturated fatty acids and maintenance of glycerolipid homeostasis.
History
Advisor
Hay, NissimChair
Hay, NissimDepartment
Biochemistry and Molecular GeneticsDegree Grantor
University of Illinois at ChicagoDegree Level
- Doctoral
Degree name
PhD, Doctor of PhilosophyCommittee Member
Kim, Jiyeon Coloff, Jonathan Benevolenskaya, Elizaveta Tyner, AngelaSubmitted date
May 2022Thesis type
application/pdfLanguage
- en
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