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TRAUGHBER_6-1-2020 (1).pdf (2.22 MB)

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The Opposing Effects of HDL Metabolism on Prostate Cancer

Traughber, Cynthia Alicia
http://orcid.org/0000-0001-6313-1129
http://rave.ohiolink.edu/etdc/view?acc_num=case1590670749249322

Abstract Details

2020, Doctor of Philosophy, Case Western Reserve University, Molecular Medicine.
Objective: Prostate cancer is the second leading cause of cancer-related deaths among men in the US. Although some reports show high concentrations of HDL cholesterol increase risk for prostate cancer, this association has not been consistent. High density lipoprotein (HDL) metabolism, is facilitated largely by scavenger receptor class B, type 1 (SR-B1) that mediates its uptake into cells, and ABCA1 that mediates its generation. SR-B1 is upregulated in prostate cancer tissue, whereas some evidence suggests that ABCA1 is downregulated in the disease. Our efforts were to determine if SR-B1-dependent HDL uptake and/or HDL biogenesis by ABCA1 export of lipids to apoA1 promotes prostate cancer cell proliferation and disease progression. Hypothesis: HDL uptake by SR-B1 drives prostate cancer proliferation and disease progression, whereas ABCA1 mediated lipid efflux decreases prostate cancer proliferation and disease progression (Fig. Abstract) Methods and Results: Here, we report that knockout (KO) of SR-B1 via CRISPR/Cas9 editing led to reduced HDL uptake into prostate cancer cells, and reduced their proliferation in response to HDL. In vivo studies using syngeneic SR-B1 wildtype (SRB1+/+) and SR-B1 KO (SR-B1-/-) prostate cancer cells in WT and apolipoprotein-AI KO (apoA1-KO) C57BL/6J mice showed that WT hosts, containing higher levels of total and HDL-cholesterol, grew larger tumors than apoA1-KO hosts with lower levels of total and HDL-cholesterol. Furthermore, SR-B1-/- prostate cancer cells formed smaller tumors in WT hosts, than SR-B1+/+ cells in same host model. Tumor volume data was overall consistent survival data. Conclusion: The results suggest that HDL through tumoral SR-B1 significantly influences the proliferation of prostate cancer cells and is a driver of the disease. Further investigation is needed to conclusively determine how HDL metabolism by ABCA1 influences prostate cancer cells and its impact on disease progression.
Jonathan Smith, PhD (Advisor)
Angela Ting, PhD (Committee Chair)
W.H. Wilson Tang, MD (Committee Member)
J. Mark Brown, PhD (Committee Member)
Nima Sharifi, MD (Committee Member)
127 p.
Cellular Biology; Medicine; Molecular Biology; Oncology
CRISPR-Cas; SCARB1; cell proliferation; high-density lipoprotein; HDL; lipoprotein metabolism; lipoprotein receptor; prostate cancer; scavenger receptor; scavenger receptor class B, type 1

Recommended Citations

Citations

  • Traughber, C. A. (2020). The Opposing Effects of HDL Metabolism on Prostate Cancer [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1590670749249322

    APA Style (7th edition)

  • Traughber, Cynthia. The Opposing Effects of HDL Metabolism on Prostate Cancer . 2020. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1590670749249322.

    MLA Style (8th edition)

  • Traughber, Cynthia. "The Opposing Effects of HDL Metabolism on Prostate Cancer ." Doctoral dissertation, Case Western Reserve University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=case1590670749249322

    Chicago Manual of Style (17th edition)

case1590670749249322
101
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This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.