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Empagliflozin drives ferroptosis in anoikis-resistant cells by activating miR-128-3p dependent pathway and inhibiting CD98hc in breast cancer
LV. Nalla, A. Khairnar
Language English Country United States
Document type Journal Article
- MeSH
- Anoikis * drug effects genetics MeSH
- Benzhydryl Compounds * pharmacology MeSH
- Ferroptosis * drug effects genetics MeSH
- Sodium-Glucose Transporter 2 Inhibitors pharmacology MeSH
- Glucosides * pharmacology MeSH
- Sodium-Phosphate Cotransporter Proteins, Type IIb MeSH
- Humans MeSH
- MicroRNAs * genetics metabolism MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Breast Neoplasms * pathology metabolism drug therapy genetics MeSH
- Lipid Peroxidation drug effects MeSH
- Reactive Oxygen Species metabolism MeSH
- Gene Expression Regulation, Neoplastic * drug effects MeSH
- Xenograft Model Antitumor Assays MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
A tumour suppressor miRNA, miR-128-3p, is widely involved in various biological processes and has been found to get downregulated in breast cancer patients. We previously published that ectopically expressed miR-128-3p suppressed migration, invasion, cell cycle arrest, and breast cancer stem cells. In the present study, we explored the role of Empagliflozin (EMPA) as a miR-128-3p functionality-mimicking drug in inducing ferroptosis by inhibiting CD98hc. Given that CD98hc is one of the proteins critical in triggering ferroptosis, we confirmed that miR-128-3p and EMPA inhibited SP1, leading to inhibition of CD98hc expression. Further, transfection with siCD98hc, miR-128-3p mimics, and inhibitors was performed to assess their involvement in the ferroptosis of anoikis-resistant cells. We proved that anoikis-resistant cells possess high ROS and iron levels. Further, miR-128-3p and EMPA treatments induced ferroptosis by inhibiting GSH and enzymatic activity of GPX4 and also induced lipid peroxidation. Moreover, EMPA suppressed bioluminescence of 4T1-Red-FLuc induced thoracic cavity, peritoneal tumour burden and lung nodules in an in-vivo metastatic model of breast cancer. Collectively, we revealed that EMPA sensitized the ECM detached cells to ferroptosis by synergically activating miR-128-3p and lowering the levels of SP1 and CD98hc, making it a potential adjunct drug for breast cancer chemotherapy.
International Clinical Research Center St Anne's University Hospital Brno Brno 602 00 Czech Republic
References provided by Crossref.org
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- $a Nalla, Lakshmi Vineela $u Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gujarat, India; Department of Pharmacology, GITAM School of Pharmacy, GITAM (Deemed to be University), Rushikonda, Visakhapatnam, Andhra Pradesh, 530045, India
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- $a A tumour suppressor miRNA, miR-128-3p, is widely involved in various biological processes and has been found to get downregulated in breast cancer patients. We previously published that ectopically expressed miR-128-3p suppressed migration, invasion, cell cycle arrest, and breast cancer stem cells. In the present study, we explored the role of Empagliflozin (EMPA) as a miR-128-3p functionality-mimicking drug in inducing ferroptosis by inhibiting CD98hc. Given that CD98hc is one of the proteins critical in triggering ferroptosis, we confirmed that miR-128-3p and EMPA inhibited SP1, leading to inhibition of CD98hc expression. Further, transfection with siCD98hc, miR-128-3p mimics, and inhibitors was performed to assess their involvement in the ferroptosis of anoikis-resistant cells. We proved that anoikis-resistant cells possess high ROS and iron levels. Further, miR-128-3p and EMPA treatments induced ferroptosis by inhibiting GSH and enzymatic activity of GPX4 and also induced lipid peroxidation. Moreover, EMPA suppressed bioluminescence of 4T1-Red-FLuc induced thoracic cavity, peritoneal tumour burden and lung nodules in an in-vivo metastatic model of breast cancer. Collectively, we revealed that EMPA sensitized the ECM detached cells to ferroptosis by synergically activating miR-128-3p and lowering the levels of SP1 and CD98hc, making it a potential adjunct drug for breast cancer chemotherapy.
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- $a Khairnar, Amit $u Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gujarat, India; International Clinical Research Center, St. Anne's University Hospital Brno, Brno, 602 00, Czech Republic; Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 753/5, Brno, 62500, Czech Republic; International Clinical Research Center, Faculty of Medicine, Masaryk University, Kamenice 753/5, Brno, 6250, Czech Republic. Electronic address: amitkhairnar520@gmail.com
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