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Identifying a novel vulnerability at the intersection of copper homeostasis and glycolytic metabolism in hepatocellular carcinoma / Caroline Ines Davis.
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- Davis, Caroline Ines, author.
- Language:
- English
- Subjects (All):
- Biochemistry.
- Cellular biology.
- Oncology.
- Biochemistry and molecular biophysics--Penn dissertations.
- Penn dissertations--biochemistry and molecular biophysics.
- Local Subjects:
- Biochemistry.
- Cellular biology.
- Oncology.
- Biochemistry and molecular biophysics--Penn dissertations.
- Penn dissertations--biochemistry and molecular biophysics.
- Genre:
- Academic theses.
- Physical Description:
- 1 online resource (157 pages)
- Contained In:
- Dissertations Abstracts International 82-07B.
- Place of Publication:
- [Philadelphia, Pennsylvania] : University of Pennsylvania ; Ann Arbor : ProQuest Dissertations & Theses, 2020.
- Language Note:
- English
- System Details:
- Mode of access: World Wide Web.
- text file
- Summary:
- Hepatocellular carcinoma (HCC), the most common primary liver cancer, of which ~800,000 new cases will be diagnosed worldwide this year, portends a five-year survival rate of merely 17% in patients with unresectable disease. This dismal prognosis is due, at least in part, from the late stage of diagnosis and the limited efficacy of systemic therapies. As a result, there is an urgent need to identify risk factors that contribute to HCC initiation and provide targetable vulnerabilities to improve patient survival. While myriad risk factors are known, elevated copper (Cu) levels in HCC patients and the incidence of hepatobiliary malignancies in Wilson disease patients, which exhibit hereditary liver Cu overload, suggests the possibility that metal accumulation promotes malignant transformation. Here we found that expression of the Cu transporter genes ATP7A, ATP7B, SLC31A1, and SLC31A2 were significantly altered in liver cancer samples and were associated with elevated Cu levels in liver cancer tissue and cells. Further analysis of genomic copy number data revealed that alterations in Cu transporter gene loci correlates with poorer survival in HCC patients. Genetic loss of the Cu importer SLC31A1 (CTR1) or pharmacologic suppression of Cu decreased the viability, clonogenic survival, and anchorage-independent growth of human HCC cell lines. Mechanistically, CTR1 knockdown or Cu chelation decreased glycolytic gene expression and downstream metabolite utilization and as a result forestall tumor cell survival after exposure to hypoxia, which mimics oxygen deprivation elicited by transarterial embolization, a standard-of-care therapy used for patients with unresectable HCC. Taken together, these findings established an association between altered Cu homeostasis and HCC and suggest that limiting Cu bioavailability may provide a new treatment strategy for HCC by restricting the metabolic reprogramming necessary for cancer cell survival.
- Notes:
- Source: Dissertations Abstracts International, Volume: 82-07, Section: B.
- Advisors: Brady, Donita C.; Committee members: Chi Dang; Kathryn Wellen; Luca Busino; Ronen Marmorstein.
- Department: Biochemistry and Molecular Biophysics.
- Ph.D. University of Pennsylvania 2020.
- Local Notes:
- School code: 0175
- ISBN:
- 9798557050906
- Access Restriction:
- Restricted for use by site license.
- This item must not be sold to any third party vendors.
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