TY - JOUR
T1 - Altered copper homeostasis underlies sensitivity of hepatocellular carcinoma to copper chelation
AU - Davis, Caroline I.
AU - Gu, Xingxing
AU - Kiefer, Ryan M.
AU - Ralle, Martina
AU - Gade, Terence P.
AU - Brady, Donita C.
N1 - Funding Information:
We thank O. Antipova for support and assistance with X-Ray Fluorescence Microscopy data collection and analysis at the Advanced Photon Source part of the Argonne National laboratory supported by the Department of Energy, Office of Basic Energy Sciences, under contract no. DE-AC02-06CH11357, A. Mancuso for materials, reagents, technical assistance, and discussions supporting this manuscript, and D. Sneddon for administrative support. This research was supported by W. W. Smith Charitable Trust #C1604 (D. C. B.), the Pilot & Feasibility Program Award (D. C. B) from National Institutes of Health (NIH) grant P30DK050306-21S1 for the University of Pennsylvania Center for Molecular Studies in Digestive and Liver Diseases, and Oregon Health and Science University Foundation (M. R.). R. M. Kiefer was supported by Howard Hughes Medical Insitute (HHMI) Medical Research Fellows Program.
Publisher Copyright:
© The Royal Society of Chemistry.
PY - 2020/12
Y1 - 2020/12
N2 - 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 was 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 correlate 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 forestalled 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.
AB - 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 was 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 correlate 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 forestalled 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.
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U2 - 10.1039/d0mt00156b
DO - 10.1039/d0mt00156b
M3 - Article
C2 - 33146201
AN - SCOPUS:85098748194
SN - 1756-5901
VL - 12
SP - 1995
EP - 2008
JO - Metallomics
JF - Metallomics
IS - 12
ER -