Atmospheric pressure gas plasma-induced colorectal cancer cell death is mediated by Nox2–ASK1 apoptosis pathways and oxidative stress is mitigated by Srx–Nrf2 anti-oxidant system

• Published in: Biochimica et biophysica acta 2014-12, Vol.1843 (12), p.2827-2837
• Main Authors: Ishaq, Musarat, Evans, Margaret D.M., Ostrikov, Kostya (Ken)
• Format: Article
• Language: English
• Subjects: Apoptosis; Apoptosis signal-regulating kinase 1 (ASK1); Atmospheric pressure gas plasmas (AGP); NADPH oxidase (Nox); Nuclear factor-erythroid 2 –related factor 2 (Nrf2); Reactive oxygen species (ROS); Sulfiredoxin (Srx)
• ISSN: 0167-4889; 0006-3002; 1879-2596
• DOI: 10.1016/j.bbamcr.2014.08.011

Atmospheric pressure gas plasma (AGP) generates reactive oxygen species (ROS) that induce apoptosis in cultured cancer cells. The majority of cancer cells develop a ROS-scavenging anti-oxidant system regulated by Nrf2, which confers resistance to ROS-mediated cancer cell death. Generation of ROS is involved in the AGP-induced cancer cell death of several colorectal cancer cells (Caco2, HCT116 and SW480) by activation of ASK1-mediated apoptosis signaling pathway without affecting control cells (human colonic sub-epithelial myofibroblasts; CO18, human fetal lung fibroblast; MRC5 and fetal human colon; FHC). However, the identity of an oxidase participating in AGP-induced cancer cell death is unknown. Here, we report that AGP up-regulates the expression of Nox2 (NADPH oxidase) to produce ROS. RNA interference designed to target Nox2 effectively inhibits the AGP-induced ROS production and cancer cell death. In some cases both colorectal cancer HT29 and control cells showed resistance to AGP treatment. Compared to AGP-sensitive Caco2 cells, HT29 cells show a higher basal level of the anti-oxidant system transcriptional regulator Nrf2 and its target protein sulfiredoxin (Srx) which are involved in cellular redox homeostasis. Silencing of both Nrf2 and Srx sensitized HT29 cells, leads to ROS overproduction and decreased cell viability. This indicates that in HT29 cells, Nrf2/Srx axis is a protective factor against AGP-induced oxidative stress. The inhibition of Nrf2/Srx signaling should be considered as a central target in drug-resistant colorectal cancer treatments. •AGP-enhanced intracellular ROS production selectively in colorectal cancer cells•AGP-activated ASK1 pathway to induce apoptosis•AGP-induced NADPH oxidase (Nox2) for ROS production•AGP-activated Nrf2–Srx oxidative stress response in HT29 colorectal cancer cells