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Author |
Kumar, N.; Perez-Novo, C.; Shaw, P.; Logie, E.; Privat-Maldonado, A.; Dewilde, S.; Smits, E.; Berghe, W.V.; Bogaerts, A. |
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Title |
Physical plasma-derived oxidants sensitize pancreatic cancer cells to ferroptotic cell death |
Type |
A1 Journal article |
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Year  |
2021 |
Publication |
Free Radical Biology And Medicine |
Abbreviated Journal |
Free Radical Bio Med |
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Volume |
166 |
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Pages |
187-200 |
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Keywords |
A1 Journal article; Plasma Lab for Applications in Sustainability and Medicine – Antwerp (PLASMANT); Center for Oncological Research (CORE) |
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Abstract |
Despite modern therapeutic advances, the survival prospects of pancreatic cancer patients remain poor, due to chemoresistance and dysregulated oncogenic kinase signaling networks. We applied a novel kinome activitymapping approach using biological peptide targets as phospho-sensors to identify vulnerable kinase dependencies for therapy sensitization by physical plasma. Ser/Thr-kinome specific activity changes were mapped upon induction of ferroptotic cell death in pancreatic tumor cells exposed to reactive oxygen and nitrogen species of plasma-treated water (PTW). This revealed a broad kinome activity response involving the CAMK, the AGC and CMGC family of kinases. This systems-level kinome network response supports stress adaptive switches between chemoresistant anti-oxidant responses of Kelch-like ECH-associated protein 1 (KEAP1)/Heme Oxygenase 1 (HMOX1) and ferroptotic cell death sensitization upon suppression of Nuclear factor (erythroid derived 2)-like 2 (NRF2) and Glutathione peroxidase 4 (GPX4). This is further supported by ex vivo experiments in the chicken chorioallantoic membrane assay, showing decreased GPX4 and Glutathione (GSH) expression as well as increased lipid peroxidation, along with suppressed BxPC-3 tumor growth in response to PTW. Taken all together, we demonstrate that plasma treated water-derived oxidants sensitize pancreatic cancer cells to ferroptotic cell death by targeting a NRF2-HMOX1-GPX4 specific kinase signaling network. |
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Wos |
000632703400001 |
Publication Date |
2021-02-23 |
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ISSN |
0891-5849 |
ISBN |
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Additional Links |
UA library record; WoS full record; WoS citing articles |
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Impact Factor |
5.606 |
Times cited |
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Open Access |
OpenAccess |
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Notes |
We gratefully acknowledge the financial support obtained from the Research Foundation Flanders (FWO), Belgium, grant number 12J5617 N and Department of Biotechnology (DBT) Ramalingaswami Re-entry Fellowship, India, grant number D.O.NO.BT/HRD/35/02/2006. We are thankful to the Laboratory of Experimental Hematology, for providing the facilities for the experimental and fluorescence microscopy work. The computational work was carried out using the Turing HPC infrastructure at the CalcUA core facility of the University of Antwerp, a division of the Flemish Supercomputer Center VSC, funded by the Hercules Foundation, the Flemish Government (department EWI), Belgium. The Kinome profiling was performed at the Epigenetic Signaling service facility (PPES-UA) funded by the Hercules Foundation and Foundation against cancer Belgium (KOTK 7872). |
Approved |
Most recent IF: 5.606 |
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Call Number |
PLASMANT @ plasmant @c:irua:176878 |
Serial |
6711 |
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