Empagliflozin drives ferroptosis in anoikis-resistant cells by activating miR-128-3p dependent pathway and inhibiting CD98hc in breast cancer
Jazyk angličtina Země Spojené státy americké Médium print-electronic
Typ dokumentu časopisecké články
PubMed
38734268
DOI
10.1016/j.freeradbiomed.2024.05.018
PII: S0891-5849(24)00453-2
Knihovny.cz E-zdroje
- Klíčová slova
- 4T1 cells, Anoikis resistance, Breast cancer, Ferroptosis, Metastasis, Reactive oxygen species,
- MeSH
- anoikis * účinky léků genetika MeSH
- benzhydrylové sloučeniny * farmakologie MeSH
- ferroptóza * účinky léků genetika MeSH
- glifloziny farmakologie MeSH
- glukosidy * farmakologie MeSH
- kotransportní proteiny pro sodík a fosfát - typ IIb MeSH
- lidé MeSH
- mikro RNA * genetika metabolismus MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory prsu * patologie metabolismus farmakoterapie genetika MeSH
- peroxidace lipidů účinky léků MeSH
- reaktivní formy kyslíku metabolismus MeSH
- regulace genové exprese u nádorů * účinky léků MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- benzhydrylové sloučeniny * MeSH
- empagliflozin MeSH Prohlížeč
- glifloziny MeSH
- glukosidy * MeSH
- kotransportní proteiny pro sodík a fosfát - typ IIb MeSH
- mikro RNA * MeSH
- MIRN128 microRNA, human MeSH Prohlížeč
- reaktivní formy kyslíku MeSH
- SLC34A2 protein, human MeSH Prohlížeč
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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