PMID- 34608499
OWN - NLM
STAT- MEDLINE
DCOM- 20220124
LR  - 20220124
IS  - 1791-3004 (Electronic)
IS  - 1791-2997 (Print)
IS  - 1791-2997 (Linking)
VI  - 24
IP  - 6
DP  - 2021 Dec
TI  - Astaxanthin induces NADPH oxidase activation and receptor‑interacting protein 
      kinase 1‑mediated necroptosis in gastric cancer AGS cells.
LID - 837 [pii]
LID - 10.3892/mmr.2021.12477 [doi]
AB  - 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.
FAU - Kim, Sori
AU  - Kim S
AD  - Department of Food and Nutrition, Brain Korea 21 FOUR Project, College of Human 
      Ecology, Yonsei University, Seoul 03722, Republic of Korea.
FAU - Lee, Hanbit
AU  - Lee H
AD  - Department of Food and Nutrition, Brain Korea 21 FOUR Project, College of Human 
      Ecology, Yonsei University, Seoul 03722, Republic of Korea.
FAU - Lim, Joo Weon
AU  - Lim JW
AD  - Department of Food and Nutrition, Brain Korea 21 FOUR Project, College of Human 
      Ecology, Yonsei University, Seoul 03722, Republic of Korea.
FAU - Kim, Hyeyoung
AU  - Kim H
AD  - Department of Food and Nutrition, Brain Korea 21 FOUR Project, College of Human 
      Ecology, Yonsei University, Seoul 03722, Republic of Korea.
LA  - eng
PT  - Journal Article
DEP - 20211005
PL  - Greece
TA  - Mol Med Rep
JT  - Molecular medicine reports
JID - 101475259
RN  - 0 (Antitubercular Agents)
RN  - 0 (Imidazoles)
RN  - 0 (Indoles)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Xanthophylls)
RN  - 0 (necrostatin-1)
RN  - 8XPW32PR7I (astaxanthine)
RN  - EC 1.1.1.27 (L-Lactate Dehydrogenase)
RN  - EC 1.6.3.- (NADPH Oxidases)
RN  - EC 2.7.- (MLKL protein, human)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.11.1 (RIPK1 protein, human)
RN  - EC 2.7.11.1 (Receptor-Interacting Protein Serine-Threonine Kinases)
SB  - IM
MH  - Adenocarcinoma/metabolism
MH  - Animals
MH  - Antitubercular Agents/pharmacology
MH  - Apoptosis
MH  - Cell Death
MH  - Cell Line, Tumor
MH  - Epithelial Cells
MH  - Humans
MH  - Imidazoles
MH  - Indoles
MH  - L-Lactate Dehydrogenase/metabolism
MH  - NADPH Oxidases/drug effects/*metabolism
MH  - *Necroptosis
MH  - Protein Kinases/metabolism
MH  - Rats
MH  - Reactive Oxygen Species/*metabolism
MH  - Receptor-Interacting Protein Serine-Threonine Kinases/*metabolism
MH  - Stomach Neoplasms/*metabolism
MH  - Xanthophylls/pharmacology
PMC - PMC8503742
OTO - NOTNLM
OT  - NADPH oxidase
OT  - astaxanthin
OT  - gastric cancer cells
OT  - reactive oxygen species
OT  - receptor interacting protein kinase 1
COIS- The authors declare that they have no competing interests.
EDAT- 2021/10/06 06:00
MHDA- 2022/01/27 06:00
PMCR- 2021/10/04
CRDT- 2021/10/05 06:42
PHST- 2021/07/21 00:00 [received]
PHST- 2021/09/22 00:00 [accepted]
PHST- 2021/10/05 06:42 [entrez]
PHST- 2021/10/06 06:00 [pubmed]
PHST- 2022/01/27 06:00 [medline]
PHST- 2021/10/04 00:00 [pmc-release]
AID - 837 [pii]
AID - MMR-24-06-12477 [pii]
AID - 10.3892/mmr.2021.12477 [doi]
PST - ppublish
SO  - Mol Med Rep. 2021 Dec;24(6):837. doi: 10.3892/mmr.2021.12477. Epub 2021 Oct 5.