Diarachidonoylphosphoethanolamine induces apoptosis of malignant pleural mesothelioma cells through a Trx/ASK1/p38 MAPK pathway

Our plain-English summary of Diarachidonoylphosphoethanolamine induces apoptosis of malignant pleural mesothelioma cells through a Trx/ASK1/p38 MAPK pathway, by A. Tsuchiya, Y. Kaku, T. Nakano, et al (Journal of Pharmacological Sciences, 2015).

The study

• Authors: A. Tsuchiya, Y. Kaku, T. Nakano, T. Nishizaki
• Journal: Journal of Pharmacological Sciences
• Published: 2015;129(3):160-8
• Cited by: 14 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

1,2-Diarachidonoyl-sn-glycero-3-phosphoethanolamine (DAPE) induces both necrosis/necroptosis and apoptosis of NCI-H28 malignant pleural mesothelioma (MPM) cells. The present study was conducted to understand the mechanism for DAPE-induced apoptosis of NCI-H28 cells. DAPE induced caspase-independent apoptosis of NCI-H28 malignant pleural mesothelioma (MPM) cells, and the effect of DAPE was prevented by antioxidants or an inhibitor of NADPH oxidase (NOX). DAPE generated reactive oxygen species (ROS) and inhibited activity of thioredoxin (Trx) reductase (TrxR). DAPE decreased an association of apoptosis signal-regulating kinase 1 (ASK1) with thioredoxin (Trx), thereby releasing ASK1. DAPE activated p38 mitogen-activated protein kinase (MAPK), which was inhibited by an antioxidant or knocking-down ASK1. In addition, DAPE-induced NCI-H28 cell death was also prevented by knocking-down ASK1. Taken together, the results of the present study indicate that DAPE stimulates NOX-mediated ROS production and suppresses TrxR activity, resulting in the decrease of reduced Trx and the dissociation of ASK1 from a complex with Trx, allowing sequential activation of ASK1 and p38 MAPK, to induce apoptosis of NCI-H28 MPM cells.

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In plain English

This laboratory study looked at how a fat-like compound called DAPE (1,2-diarachidonoyl-sn-glycero-3-phosphoethanolamine) causes programmed cell death (apoptosis) in NCI-H28, a human malignant pleural mesothelioma cell line grown in dishes. It did not study asbestos exposure or patients. DAPE reduced cell survival, and the effect grew with dose and with treatment time (24 to 48 hours). It increased signs of apoptosis without significantly activating the caspase enzymes usually involved. Two antioxidants, GSH and NAC, and blockers of the enzyme NOX and of Rac reduced this cell death. DAPE raised reactive oxygen species and cut thioredoxin reductase activity to about 60% of starting levels at 120 minutes. Binding of thioredoxin to the signaling protein ASK1 fell to almost half of starting levels. DAPE increased activation of ASK1 and p38 MAPK. Silencing ASK1 clearly inhibited the p38 increase and significantly reduced cell death. The authors concluded that DAPE induces apoptosis in these cells mainly through an ASK1/MKK(3/6)/p38 MAPK pathway. They left open why MKK3 was not significantly activated.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: laboratory (in vitro) experiments on a cultured human cancer cell line
• Who was studied: NCI-H28 malignant pleural mesothelioma cells, a cell line bought from the American Type Culture Collection; most measurements were based on 4 independent experiments
• Exposure: Treatment with DAPE, a phosphatidylethanolamine. Most experiments used a concentration printed as 100 mM; the unit symbol may be scan-damaged. Some experiments added antioxidants (GSH, NAC), a NOX inhibitor (VAS) or a Rac inhibitor (NSC), or silenced ASK1. Asbestos was not tested.
• Main results:
  • DAPE reduced NCI-H28 cell viability depending on treatment time (24 to 48 h) and concentration, and increased TUNEL-positive (apoptotic) cells
  • DAPE caused no significant activation of caspase-3, -4, -8 or -9; the authors interpreted the cell death as caspase-independent apoptosis
  • DAPE-induced cell death was significantly inhibited by the antioxidant GSH, and was also prevented by NAC and attenuated by the NOX inhibitor VAS and the Rac inhibitor NSC
  • DAPE produced reactive oxygen species (ROS) in NCI-H28 cells; this was inhibited by GSH and abrogated by VAS
  • DAPE suppressed thioredoxin reductase (TrxR) activity, reaching approximately 60% of basal levels at 120 min
  • DAPE decreased the association of thioredoxin with ASK1, reaching almost half of basal levels at 120 min
  • DAPE increased ASK1 phosphorylation and produced a striking increase in p38 MAPK phosphorylation. It did not significantly increase MKK3 phosphorylation and did not enhance ERK1/2 phosphorylation.
  • DAPE significantly increased JNK phosphorylation only at 30-minute treatment
  • Silencing ASK1 clearly inhibited the DAPE-induced p38 MAPK increase and significantly prevented DAPE-induced cell death
• The authors' conclusion: The authors concluded that DAPE induces apoptosis of NCI-H28 cells dominantly through an ASK1/MKK(3/6)/p38 MAPK pathway. In their account, NOX-generated ROS suppress TrxR and release ASK1 from thioredoxin. They suggested this may establish a new apoptotic pathway relevant to DAPE signaling.
• Limitations the authors state:
  • The authors raised unanswered questions: why MKK3 was not significantly activated despite p38 MAPK activation, and why GSH did not inhibit ASK1 activation. They suggested there may be an additional direct p38 MAPK activation pathway.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Apoptosis, Pleural Mesothelioma, Necrosis, Reactive Oxygen Species (ROS).

Related studies

• Diarachidonoylphosphoethanolamine induces necrosis/necroptosis of malignant pleural mesothelioma cells — Y. Kaku, A. Tsuchiya, et al. (2015)
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• Licochalcone A induces apoptosis in malignant pleural mesothelioma through downregulation of Sp1 and subsequent activation of mitochondria-related apoptotic pathway — K.H. Kim, G. Yoon, et al. (2015)
• Manumycin A induces apoptosis in malignant pleural mesothelioma through regulation of Sp1 and activation of the mitochondria-related apoptotic pathway — K.H. Kim, J.I. Chae, et al. (2016)
• TRAIL and proteasome inhibitors combination induces a robust apoptosis in human malignant pleural mesothelioma cells through Mcl-1 and Akt protein cleavages — B.Z. Yuan, J. Chapman, et al. (2013)
• Pemetrexed induces apoptosis in malignant mesothelioma and lung cancer cells through activation of reactive oxygen species and inhibition of sirtuin 1 — K.E. Hwang, Y.S. Kim, et al. (2015)

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