Efﬁcacy of glucose transporter inhibitors for the treatment of ERRα-overexpressed colorectal cancer
Background: Colorectal cancer is the most-incidence associated extremely high mortality rate worldwide. The overexpression of estrogen-related receptor α (ERRα) is contributing to a poor prognosis. Obtaining a better understanding of the mechanisms of ERRα in colorectal cancer is important for developing cancer therapies. Methods: Western blotting and qRT-PCR were used to determine the protein and mRNA levels of ERRα, OUTB1, and solute carrier family 7 member 11 (SLC7A11) in HCT-116 cells. Short hairpin RNA (shRNA) was used to knockdown ERRα in HCT-116 cells. The level of reactive oxygen species (ROS), the nicotinamide adenine dinucleotide phosphate NADP+/NADPH, and the oxidized glutathione (GSSG)/reduced glutathione (GSH) ratio were measured by HPLC-MS to determine the redox state in HCT-116 cells. Lastly, tumor xenograft experiments were carried out to determine the effect of glucose transporter (GLUT) inhibitor. Results: Knockdown of ERRα decreased the expression of OTUB1 and SLC7A11 in HCT-116 cells. SLC7A11 overexpression induced NADPH-dependent redox system collapse. Aberrant expression of ERRα significantly reduced NADPH level and resulted in collapse of the redox system under glucose deprivation. Furthermore, ERR overexpression of ERRα sensitized cancer cells to inhibition of GLUTs. Treatment with GLUT inhibitor significantly reduced tumor volume after 6 weeks of tumor xenograft experiment. Our study demonstrates that the over-expression of ERRα causes redox system collapses via regulating the expressions of OUTB1 and SLC7A11. Conclusion: Up-regulation of SLC7A11 mediates the disruption of cell metabolism and the balance of redox state in colorectal cancer. Additionally, the GLUT inhibitor significantly reduces colorectal tumor volume, suggesting that the GLUT inhibitor could serve as a potential therapy for colorectal treatment.
Copyright (c) 2022 Miao Zhao, Cairong Xu, Hui Zhu
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Acta Biochimica Polonica is an open access quarterly and publishes four issues a year. All contents are distributed under the Creative Commons Attribution-ShareAlike 4.0 International (CC BY-SA 4.0) license. Everybody may use the content following terms: Attribution — You must give appropriate credit, provide a link to the license, and indicate if changes were made, ShareAlike — If you remix, transform, or build upon the material, you must distribute your contributions under the same license as the original. There are no additional restrictions — You may not apply legal terms or technological measures that legally restrict others from doing anything the license permits.
Copyright for all published papers © stays with the authors.
Copyright for the journal: © Polish Biochemical Society.