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Molecular mechanisms of nemorosone-induced ferroptosis in cancer cells

(2023) CELLS. 12(5).
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Abstract
Ferroptosis is an iron-dependent cell death-driven by excessive peroxidation of polyunsaturated fatty acids (PUFAs) of membranes. A growing body of evidence suggests the induction of ferroptosis as a cutting-edge strategy in cancer treatment research. Despite the essential role of mitochondria in cellular metabolism, bioenergetics, and cell death, their function in ferroptosis is still poorly understood. Recently, mitochondria were elucidated as an important component in cysteine-deprivation-induced (CDI) ferroptosis, which provides novel targets in the search for new ferroptosis-inducing compounds (FINs). Here, we identified the natural mitochondrial uncoupler nemorosone as a ferroptosis inducer in cancer cells. Interestingly, nemorosone triggers ferroptosis by a double-edged mechanism. In addition to decreasing the glutathione (GSH) levels by blocking the System xc cystine/glutamate antiporter (SLC7A11), nemorosone increases the intracellular labile Fe2+ pool via heme oxygenase-1 (HMOX1) induction. Interestingly, a structural variant of nemorosone (O-methylated nemorosone), having lost the capacity to uncouple mitochondrial respiration, does not trigger cell death anymore, suggesting that the mitochondrial bioenergetic disruption via mitochondrial uncoupling is necessary for nemorosone-induced ferroptosis. Our results open novel opportunities for cancer cell killing by mitochondrial uncoupling-induced ferroptosis.
Keywords
General Medicine, nemorosone, ferroptosis, mitochondrial uncoupling, fibrosarcoma, neuroblastoma, CYTOTOXIC ACTIVITY, CUBAN PROPOLIS, FLORAL RESINS, DEATH, CLUSIA, NRF2, GLUTATHIONE, APOPTOSIS, PATHWAY, GPX4

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MLA
Fernández-Acosta, Roberto, et al. “Molecular Mechanisms of Nemorosone-Induced Ferroptosis in Cancer Cells.” CELLS, vol. 12, no. 5, 2023, doi:10.3390/cells12050735.
APA
Fernández-Acosta, R., Hassannia, B., Caroen, J., Wiernicki, B., Alvarez-Alminaque, D., Verstraeten, B., … Pardo-Andreu, G. L. (2023). Molecular mechanisms of nemorosone-induced ferroptosis in cancer cells. CELLS, 12(5). https://doi.org/10.3390/cells12050735
Chicago author-date
Fernández-Acosta, Roberto, Behrouz Hassannia, Jurgen Caroen, Bartosz Wiernicki, Daniel Alvarez-Alminaque, Bruno Verstraeten, Johan Van der Eycken, Peter Vandenabeele, Tom Vanden Berghe, and Gilberto L. Pardo-Andreu. 2023. “Molecular Mechanisms of Nemorosone-Induced Ferroptosis in Cancer Cells.” CELLS 12 (5). https://doi.org/10.3390/cells12050735.
Chicago author-date (all authors)
Fernández-Acosta, Roberto, Behrouz Hassannia, Jurgen Caroen, Bartosz Wiernicki, Daniel Alvarez-Alminaque, Bruno Verstraeten, Johan Van der Eycken, Peter Vandenabeele, Tom Vanden Berghe, and Gilberto L. Pardo-Andreu. 2023. “Molecular Mechanisms of Nemorosone-Induced Ferroptosis in Cancer Cells.” CELLS 12 (5). doi:10.3390/cells12050735.
Vancouver
1.
Fernández-Acosta R, Hassannia B, Caroen J, Wiernicki B, Alvarez-Alminaque D, Verstraeten B, et al. Molecular mechanisms of nemorosone-induced ferroptosis in cancer cells. CELLS. 2023;12(5).
IEEE
[1]
R. Fernández-Acosta et al., “Molecular mechanisms of nemorosone-induced ferroptosis in cancer cells,” CELLS, vol. 12, no. 5, 2023.
@article{01GWSGKF33TP2ER2WDKPQ3DMHV,
  abstract     = {{Ferroptosis is an iron-dependent cell death-driven by excessive peroxidation of polyunsaturated fatty acids (PUFAs) of membranes. A growing body of evidence suggests the induction of ferroptosis as a cutting-edge strategy in cancer treatment research. Despite the essential role of mitochondria in cellular metabolism, bioenergetics, and cell death, their function in ferroptosis is still poorly understood. Recently, mitochondria were elucidated as an important component in cysteine-deprivation-induced (CDI) ferroptosis, which provides novel targets in the search for new ferroptosis-inducing compounds (FINs). Here, we identified the natural mitochondrial uncoupler nemorosone as a ferroptosis inducer in cancer cells. Interestingly, nemorosone triggers ferroptosis by a double-edged mechanism. In addition to decreasing the glutathione (GSH) levels by blocking the System xc cystine/glutamate antiporter (SLC7A11), nemorosone increases the intracellular labile Fe2+ pool via heme oxygenase-1 (HMOX1) induction. Interestingly, a structural variant of nemorosone (O-methylated nemorosone), having lost the capacity to uncouple mitochondrial respiration, does not trigger cell death anymore, suggesting that the mitochondrial bioenergetic disruption via mitochondrial uncoupling is necessary for nemorosone-induced ferroptosis. Our results open novel opportunities for cancer cell killing by mitochondrial uncoupling-induced ferroptosis.}},
  articleno    = {{735}},
  author       = {{Fernández-Acosta, Roberto and Hassannia, Behrouz and Caroen, Jurgen and Wiernicki, Bartosz and Alvarez-Alminaque, Daniel and Verstraeten, Bruno and Van der Eycken, Johan and Vandenabeele, Peter and Vanden Berghe, Tom and Pardo-Andreu, Gilberto L.}},
  issn         = {{2073-4409}},
  journal      = {{CELLS}},
  keywords     = {{General Medicine,nemorosone,ferroptosis,mitochondrial uncoupling,fibrosarcoma,neuroblastoma,CYTOTOXIC ACTIVITY,CUBAN PROPOLIS,FLORAL RESINS,DEATH,CLUSIA,NRF2,GLUTATHIONE,APOPTOSIS,PATHWAY,GPX4}},
  language     = {{eng}},
  number       = {{5}},
  pages        = {{22}},
  title        = {{Molecular mechanisms of nemorosone-induced ferroptosis in cancer cells}},
  url          = {{http://doi.org/10.3390/cells12050735}},
  volume       = {{12}},
  year         = {{2023}},
}

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