TY - JOUR
T1 - Targeting Glutamine Metabolism with a Novel Naþ/Kþ-ATPase Inhibitor RX108 in Hepatocellular Carcinoma
AU - Wei, Daoyan
AU - Chen, Dongmei
AU - Mou, Hongyuan
AU - Chakraborty, Sharmistha
AU - Wei, Bo
AU - Tan, Lin
AU - Lorenzi, Philip L.
AU - Qian, Xiangping
AU - Yang, Peiying
N1 - Funding Information:
This study was partially supported by a research grant from NeuPharma (San Mateo, CA). It is also supported by the NIH/NCI under award number P30CA016672 and used the MD Anderson Flow Cytometry and Cellular Imaging Core Facility (for cell-cycle and apoptosis analysis) and Metabo-lomics Core Facility (for metabolic tracing analysis). We thank Donald Norwood of MD Anderson Editing Services, Research Medical Library for editing the manuscript.
Funding Information:
D. Wei reports grants from NeuPharma, NIH/NCI; and other support from MD Anderson Core Labs during the conduct of the study. X. Qian reports a patent for US 8,334,376 B2 issued. P. Yang reports grants from NeuPharma; and
Funding Information:
This study was partially supported by a research grant from NeuPharma (San Mateo, CA). It is also supported by the NIH/NCI under award number P30CA016672 and used the MD Anderson Flow Cytometry and Cellular Imaging Core Facility (for cell-cycle and apoptosis analysis) and Metabolomics Core Facility (for metabolic tracing analysis). We thank Donald Norwood of MD Anderson Editing Services, Research Medical Library for editing the manuscript.
Publisher Copyright:
© 2023 American Association for Cancer Research.
PY - 2023/6
Y1 - 2023/6
N2 - The poor prognosis and limited therapeutic options for human hepatocellular carcinoma (HCC), the most common form of liver cancer, highlight the urgent need to identify novel therapeutic modalities. Here, we describe the antitumor activity and underlying molecular mechanisms of a novel Naþ/KþATPase inhibitor RX108 in human HCC cells and its xenograft model. RX108 dose-dependently inhibited HCC cell proliferation in vitro and tumor growth in a xenograft mouse model, and that the inhibition was associated with induction of apoptosis. Mechanistically, RX108 significantly downregulated alanine serine cysteine transporter 2 (ASCT2) protein expression and reduced glutamine and glutamate concentration in HCC cells and tumors. In addition, RX108 exposure led to a significant decrease in cell energy metabolism in Huh7 and Hep3B cells, including decreased levels of glutathione, NADH, NADPH, and mitochondrial respiration oxygen consumption rate. Furthermore, HCC cells exhibited evidence of glutamine addiction; the antiproliferative effect of RX108 was dependent on glutamine transport. Clinically, elevated ASCT2 mRNA expression in HCCs was associated with unfavorable survival. Taken together, these findings reveal a novel approach to target glutamine metabolism through inhibiting Naþ/Kþ-ATPase and provide a rationale for using RX108 to treat HCC in patients whose tumors express ASCT2 at high levels. RX108 is currently under clinical development.
AB - The poor prognosis and limited therapeutic options for human hepatocellular carcinoma (HCC), the most common form of liver cancer, highlight the urgent need to identify novel therapeutic modalities. Here, we describe the antitumor activity and underlying molecular mechanisms of a novel Naþ/KþATPase inhibitor RX108 in human HCC cells and its xenograft model. RX108 dose-dependently inhibited HCC cell proliferation in vitro and tumor growth in a xenograft mouse model, and that the inhibition was associated with induction of apoptosis. Mechanistically, RX108 significantly downregulated alanine serine cysteine transporter 2 (ASCT2) protein expression and reduced glutamine and glutamate concentration in HCC cells and tumors. In addition, RX108 exposure led to a significant decrease in cell energy metabolism in Huh7 and Hep3B cells, including decreased levels of glutathione, NADH, NADPH, and mitochondrial respiration oxygen consumption rate. Furthermore, HCC cells exhibited evidence of glutamine addiction; the antiproliferative effect of RX108 was dependent on glutamine transport. Clinically, elevated ASCT2 mRNA expression in HCCs was associated with unfavorable survival. Taken together, these findings reveal a novel approach to target glutamine metabolism through inhibiting Naþ/Kþ-ATPase and provide a rationale for using RX108 to treat HCC in patients whose tumors express ASCT2 at high levels. RX108 is currently under clinical development.
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U2 - 10.1158/1535-7163.MCT-22-0490
DO - 10.1158/1535-7163.MCT-22-0490
M3 - Article
C2 - 36780187
AN - SCOPUS:85160965149
SN - 1535-7163
VL - 22
SP - 693
EP - 705
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 6
ER -