Open Access

Astaxanthin induces NADPH oxidase activation and receptor‑interacting protein kinase 1‑mediated necroptosis in gastric cancer AGS cells

  • Authors:
    • Sori Kim
    • Hanbit Lee
    • Joo Weon Lim
    • Hyeyoung Kim
  • View Affiliations

  • Published online on: October 4, 2021     https://doi.org/10.3892/mmr.2021.12477
  • Article Number: 837
  • Copyright: © Kim et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Astaxanthin (ASX), a red‑colored xanthophyll carotenoid, functions as an antioxidant or pro‑oxidant. ASX displays anticancer effects by reducing or increasing oxidative stress. Reactive oxygen species (ROS) promote cancer cell death by necroptosis mediated by receptor‑interacting protein kinase 1 (RIP1) and RIP3. NADPH oxidase is a major source of ROS that may promote necroptosis in some cancer cells. The present study aimed to investigate whether ASX induces necroptosis by increasing NADPH oxidase activity and ROS levels in gastric cancer AGS cells. AGS cells were treated with ASX with or without ML171 (NADPH oxidase 1 specific inhibitor), N‑acetyl cysteine (NAC; antioxidant), z‑VAD (pan‑caspase inhibitor) or Necrostatin‑1 (Nec‑1; a specific inhibitor of RIP1). As a result, ASX increased NADPH oxidase activity, ROS levels and cell death, and these effects were suppressed by ML171 and NAC. Furthermore, ASX induced RIP1 and RIP3 activation, ultimately inducing mixed lineage kinase domain‑like protein (MLKL) activation, lactate dehydrogenase (LDH) release and cell death. Moreover, the ASX‑induced decrease in cell viability was reversed by Nec‑1 treatment and RIP1 siRNA transfection, but not by z‑VAD. ASX did not increase the ratio of apoptotic Bax/anti‑apoptotic Bcl‑2, the number of Annexin V‑positive cells, or caspase‑9 activation, which are apoptosis indices. In conclusion, ASX induced necroptotic cell death by increasing NADPH oxidase activity, ROS levels, LDH release and the number of propidium iodide‑positive cells, as well as activating necroptosis‑regulating proteins, RIP1/RIP3/MLKL, in gastric cancer AGS cells. The results of this study demonstrated the necroptotic effect of ASX on gastric cancer AGS cells, which required NADPH oxidase activation and RIP1/RIP3/MLKL signaling in vitro.
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December-2021
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Spandidos Publications style
Kim S, Lee H, Lim JW and Kim H: Astaxanthin induces NADPH oxidase activation and receptor‑interacting protein kinase 1‑mediated necroptosis in gastric cancer AGS cells. Mol Med Rep 24: 837, 2021
APA
Kim, S., Lee, H., Lim, J.W., & Kim, H. (2021). Astaxanthin induces NADPH oxidase activation and receptor‑interacting protein kinase 1‑mediated necroptosis in gastric cancer AGS cells. Molecular Medicine Reports, 24, 837. https://doi.org/10.3892/mmr.2021.12477
MLA
Kim, S., Lee, H., Lim, J. W., Kim, H."Astaxanthin induces NADPH oxidase activation and receptor‑interacting protein kinase 1‑mediated necroptosis in gastric cancer AGS cells". Molecular Medicine Reports 24.6 (2021): 837.
Chicago
Kim, S., Lee, H., Lim, J. W., Kim, H."Astaxanthin induces NADPH oxidase activation and receptor‑interacting protein kinase 1‑mediated necroptosis in gastric cancer AGS cells". Molecular Medicine Reports 24, no. 6 (2021): 837. https://doi.org/10.3892/mmr.2021.12477