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The Role of Purine Nucleotide Metabolism in Renal Cell Carcinoma Migration

Wolfe, Kara
http://orcid.org/0000-0002-8192-3645
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1563872926565308

Abstract Details

2019, PhD, University of Cincinnati, Medicine: Cancer and Cell Biology.
The rate-limiting GTP-biosynthetic enzyme inosine 5’-monophosphate dehydrogenase (IMPDH) has been implicated in the tumorigenesis and progression of multiple cancer types. Overexpression of the IMPDH2 isozyme is correlated with worse prognosis, the presence of metastatic disease, and disease progression and is also readily inhibited by the FDA-approved drug mycophenolic acid (MPA), making IMPDH a potential therapeutic target for cancer therapy. In recent years, the GTP biosynthetic pathway has been increasingly associated with cell migration, the important first step to cancer metastasis. How IMPDH promotes cancer cell migration has not been extensively studied. In this thesis, the role of IMPDH in renal cell carcinoma (RCC) migration is assessed. RCC has a very high rate of metastasis, with nearly 25% of patients presenting with metastatic disease at the time of diagnosis and another 20-30% progressing to metastatic disease following nephrectomy. Understanding the underlying mechanisms of RCC migration may enhance our ability to develop effective therapeutics for preventing and treating RCC metastasis. Chapter 1 and chapter 2 encompass the importance of purine nucleotide biosynthesis in cancer, including an explanation of the enzymes involved in biosynthesis and the literature connecting their activities with tumorigenesis, as well as background information regarding RCC subtypes, metabolism, staging and diagnosis, and an introduction to the current therapeutic options for patients with metastatic disease. In chapter 3 of this thesis, the role of IMPDH in RCC proliferation and migration in vitro is reported. IMPDH knockout or inhibition in RCC cell lines impedes both proliferation and migration ability on a global level. Chapter 4 delves deeper into the subcellular localization of the entire purine biosynthesis pathway and its role in cell migration. In this thesis, we report the novel finding that enzymes involved in the purine de novo pathway, ATP and GTP biosynthetic branches, and the salvage pathway are localized at the leading edge of migrating RCC cells. This localization appears to form a microcompartment of purine nucleotide metabolism at the leading edge. Metabolic compartmentalization is a rapidly expanding field. Our understanding of microcompartmentalization is relatively limited to the tricarboxylic acid cycle and glycolysis, as well as some mammalian target of rapamycin (mTOR) signaling components associated with the lysosomes. The finding of IMPDH and purine biosynthetic enzyme compartmentalization at the leading edge opens a new window into understanding the metabolic input involved in cell migration and potential therapeutic options for targeting this migration in patients with advanced or metastatic disease. It is possible that localized purine biosynthesis is occurring to fuel cell polarization and the signaling and cytoskeletal dynamics required for migration and, ultimately, metastasis. In chapter 5, we discuss these conclusions and future directions for assessing their validity in our RCC models. The findings presented in this thesis lay the path for more advanced studies into metabolic compartmentalization during cell migration and the potential therapeutic advantage in inhibiting this pathway to prevent cancer migration and metastasis.
Atsuo Sasaki, Ph.D. (Committee Chair)
Maria Czyzyk-Krzeska, M.D. (Committee Member)
Francis McCormack, M.D. (Committee Member)
Satoshi Namekawa, Ph.D. (Committee Member)
Susan Waltz, Ph.D. (Committee Member)
169 p.
Biology
IMPDH; Purine nucleotide; Renal cell carcinoma; Migration; Compartmentalization; Nucleotide biosynthesis

Recommended Citations

Citations

  • Wolfe, K. (2019). The Role of Purine Nucleotide Metabolism in Renal Cell Carcinoma Migration [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1563872926565308

    APA Style (7th edition)

  • Wolfe, Kara. The Role of Purine Nucleotide Metabolism in Renal Cell Carcinoma Migration. 2019. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1563872926565308.

    MLA Style (8th edition)

  • Wolfe, Kara. "The Role of Purine Nucleotide Metabolism in Renal Cell Carcinoma Migration." Doctoral dissertation, University of Cincinnati, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1563872926565308

    Chicago Manual of Style (17th edition)

ucin1563872926565308
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© 2019, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.