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Physical plasma-derived oxidants sensitize pancreatic cancer cells to ferroptotic cell death

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 activity-mapping approach using biological peptide targets as phospho-sensors to identify vuln...

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Bibliographic Details
Published in:Free radical biology & medicine 2021-04, Vol.166, p.187-200
Main Authors: Kumar, Naresh, Perez-Novo, Claudina, Shaw, Priyanka, Logie, Emilie, Privat-Maldonado, Angela, Dewilde, Sylvia, Smits, Evelien, Berghe, Wim Vanden, Bogaerts, Annemie
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Language:English
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Summary: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 activity-mapping 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. [Display omitted] •Today, the survival prospects of pancreatic cancer patients remain poor, due to chemoresistance and dysregulated oncogenic kinase signaling networks.•Physical plasma-derived oxidants (reactive oxygen and nitrogen species) sensitize chemoresistant pancreatic cancer cells in vitro and in ovo.•Physical plasma-derived oxidants eradicate chemoresistant cancer cells by iron-dependent ferroptosis, driven by excessive lipid peroxidation.•Physical plasma-derived oxidants induce ferroptosis by CAMK, the AGC and CMGC kinome regulation of NRF2-HMOX1-GPX4 protein functions.
ISSN:0891-5849
1873-4596
DOI:10.1016/j.freeradbiomed.2021.02.026