Skip to Main Content
 

Global Search Box

 
 
 
 

Files

File List


36336.pdf (9.62 MB)

ETD Abstract Container

Abstract Header

Mechanisms regulating cancer cell sensitivity and acquired resistance to Stearoyl-CoA Desaturase inhibition

Oatman, Nicole
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1573572568302598

Abstract Details

2019, PhD, University of Cincinnati, Medicine: Cancer and Cell Biology.
Glioblastoma (GBM) is the most common malignant glioma in adults. It is highly infiltrative and incurable. Several key enzymes of the lipogenic pathway are implicated in the pathogenesis of GBM. One such critical lipogenic enzyme is Stearoyl-CoA Desaturase (SCD). SCD catalyzes the rate-limiting step in the formation of monounsaturated fatty acids (MUFAS), specifically oleoyl-CoA and palmitoleoyl-CoA from saturated fatty acids (SFA) stearoyl-CoA and palmitoyl-CoA, respectively. MUFAs can serve as substrates for the synthesis of various kinds of lipids including phospholipids and triglycerides needed for cancer cell replication to sustain the increasing demand for lipids. SCD is highly expressed in a variety of cancers, however this thesis demonstrates that SCD expression is surprisingly suppressed in some cancers including GBM and melanoma such that there are two subgroups: one subgroup that expresses SCD (SCD-expressing) and one that expresses little or no SCD (SCD-non-expressing). While the SCD-expressing subgroup is sensitive to SCD inhibition, the SCD-non-expressing group is not. Mice transplanted intracranially with SCD-expressing GBM cells, survive longer with SCD inhibitor than vehicle treated mice. Additionally, SCD inhibitor treatment normalizes tumor blood vessels, suggesting a secondary effect on tumor vasculature. Deletions (as part of chromosome 10q loss) and mutations in the tumor suppressor gene PTEN are frequent in GBM and melanoma. When looking into why the SCD-non-expressing subgroup expressed little or no SCD, we found that one SCD allele is co-deleted with PTEN and the trans allele is methylated. In the SCD-expressing subgroup, prolonged exposure to the SCD inhibitor results in acquired resistance (AqR) in both GBM and melanoma. Indeed, AqR cells show SCD up-regulation both at the mRNA and protein levels in vitro and in tumors of mice treated with the SCD inhibitor. RNA-Seq and functional proteomics analysis revealed that the acute phase response signaling pathway, comprising FOS, is also up-regulated in AqR cells. AqR cells show up-regulation of FOSB both at the mRNA and protein levels in vitro and in tumors of mice treated with the SCD inhibitor. FOSB knockdown in the AqR cells results in decreased viability and re-sensitization to the SCD inhibitor. We show that there is a chromatin reorganization in the AqR cells, which suggests that newly open sites allow for FOSB to bind and regulate SCD resulting in SCD up-regulation and development of SCD inhibitor resistance. Taken together, our findings suggest that SCD expression status could be used to stratify patients for SCD inhibitor therapy.
Biplab Dasgupta, Ph.D. (Committee Chair)
Kakajan Komurov, Ph.D. (Committee Member)
Ashish Kumar, M.D. Ph.D. (Committee Member)
Nancy Ratner, Ph.D. (Committee Member)
Ronald Waclaw, Ph.D. (Committee Member)
156 p.
Oncology

Recommended Citations

Citations

  • Oatman, N. (2019). Mechanisms regulating cancer cell sensitivity and acquired resistance to Stearoyl-CoA Desaturase inhibition [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1573572568302598

    APA Style (7th edition)

  • Oatman, Nicole. Mechanisms regulating cancer cell sensitivity and acquired resistance to Stearoyl-CoA Desaturase inhibition. 2019. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1573572568302598.

    MLA Style (8th edition)

  • Oatman, Nicole. "Mechanisms regulating cancer cell sensitivity and acquired resistance to Stearoyl-CoA Desaturase inhibition." Doctoral dissertation, University of Cincinnati, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1573572568302598

    Chicago Manual of Style (17th edition)

ucin1573572568302598
258
© 2019, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.