Physical plasma-derived oxidants sensitize pancreatic cancer cells to ferroptotic cell death
Autor: | Wim Vanden Berghe, Evelien Smits, Emilie Logie, Angela Privat-Maldonado, Priyanka Shaw, Naresh Kumar, Annemie Bogaerts, Claudina Perez-Novo, Sylvia Dewilde |
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Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
Programmed cell death HMOX1 NF-E2-Related Factor 2 Serine threonine protein kinase GPX4 Biochemistry 03 medical and health sciences 0302 clinical medicine Physiology (medical) Pancreatic cancer medicine Humans Kinome Biology CAMK Kelch-Like ECH-Associated Protein 1 Cell Death Chemistry Kinase Oxidants medicine.disease Pancreatic Neoplasms 030104 developmental biology Cancer research Human medicine Reactive Oxygen Species 030217 neurology & neurosurgery |
Zdroj: | Free radical biology and medicine |
ISSN: | 0891-5849 |
DOI: | 10.1016/j.freeradbiomed.2021.02.026 |
Popis: | 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. |
Databáze: | OpenAIRE |
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