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<p>Cold atmospheric plasma (CAP) is an emerging non-invasive cancer treatment modality, yet its ability to elicit non-targeted bystander effects has not been established. In this study, lung adenocarcinoma A549 cells were exposed to CAP for 5&#xa0;min, and the conditioned medium was transferred to unexposed (bystander) cells. Both direct CAP-exposed and bystander cells showed similar decrease in clonogenic survival, increase in DNA damage (γ-H2AX foci), and activation of DNA-damage-response (DDR) signalling, providing clear evidence of CAP-induced bystander effect. Label-free LC-MS/MS revealed modulation of both shared and unique responses in direct CAP-exposed and bystander cells. Over-representation analysis showed that direct-exposure activated an ER-stress response through unfolded protein response and chaperone mediated protein folding pathways. Conversely, bystander cells showed an adaptive stress response via protein ubiquitination/deubiquitination processes and, NF-κB and MAPK cascades. Mechanistically, pharmacological inhibition of ATR (with NU6027), but not ATM (with KU-55933) significantly attenuated bystander response. This indicates a non-canonical ATR mediated model of bystander CAP signaling, possibly through release of soluble factors to neighbouring cells. Collectively, the findings challenge the classical ‘direct-action’ paradigm by demonstrating ionizing radiation-like bystander effects for non-ionizing CAP and highlights ATR as a potential therapeutic target to improve the efficacy of CAP-based cancer treatment.</p>

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Non-canonical ATR signaling mediates direct and bystander cold atmospheric plasma-induced stress responses in A549 lung adenocarcinoma cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月8日

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  • Somnath Ghosh,
  • S. Nishad,
  • Akshay Vaid,
  • Niharika Nema Baijal,
  • Anand Visani,
  • Ramkrishna Rane,
  • Alphonsa Joseph,
  • Anu Ghosh

摘要

Cold atmospheric plasma (CAP) is an emerging non-invasive cancer treatment modality, yet its ability to elicit non-targeted bystander effects has not been established. In this study, lung adenocarcinoma A549 cells were exposed to CAP for 5 min, and the conditioned medium was transferred to unexposed (bystander) cells. Both direct CAP-exposed and bystander cells showed similar decrease in clonogenic survival, increase in DNA damage (γ-H2AX foci), and activation of DNA-damage-response (DDR) signalling, providing clear evidence of CAP-induced bystander effect. Label-free LC-MS/MS revealed modulation of both shared and unique responses in direct CAP-exposed and bystander cells. Over-representation analysis showed that direct-exposure activated an ER-stress response through unfolded protein response and chaperone mediated protein folding pathways. Conversely, bystander cells showed an adaptive stress response via protein ubiquitination/deubiquitination processes and, NF-κB and MAPK cascades. Mechanistically, pharmacological inhibition of ATR (with NU6027), but not ATM (with KU-55933) significantly attenuated bystander response. This indicates a non-canonical ATR mediated model of bystander CAP signaling, possibly through release of soluble factors to neighbouring cells. Collectively, the findings challenge the classical ‘direct-action’ paradigm by demonstrating ionizing radiation-like bystander effects for non-ionizing CAP and highlights ATR as a potential therapeutic target to improve the efficacy of CAP-based cancer treatment.