Arsenic trioxide induces apoptosis through JNK and ERK in human mesothelioma cells

Our plain-English summary of Arsenic trioxide induces apoptosis through JNK and ERK in human mesothelioma cells, by R. Eguchi, Y. Fujimori, H. Takeda, et al (Journal of Cellular Physiology, 2011).

The study

• Authors: R. Eguchi, Y. Fujimori, H. Takeda, C. Tabata, T. Ohta, K. Kuribayashi, K. Fukuoka, T. Nakano
• Journal: Journal of Cellular Physiology
• Published: 2011;226(3):762-8
• Cited by: 48 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant mesothelioma is an aggressive tumor of serosal surfaces, which is refractory to current treatment options. Arsenic trioxide (As2O3) is used clinically to treat acute promyelocytic leukemia, and also to inhibit proliferation of several solid tumors including hepatoma, esophageal, and gastric cancer in vitro. Here we found that As2O3 inhibited cell viability of a mesothelioma cell line, NCI-H2052. As2O3 induced apoptosis of NCI-H2052 cells, which was accompanied by activation of c-Jun NH2-terminal kinase (JNK)1/2, extracellular signal-regulated kinase (ERK)1/2, and caspase-3. zVAD-fmk, a broad-spectrum caspase inhibitor, inhibited As2O3-induced apoptosis and activation of caspase-3, but not that of JNK1/2 and ERK1/2. Small interfering RNAs (siRNAs) targeting JNK1/2 suppressed As2O3-induced caspase-3 activation and apoptosis, indicating that JNK1/2 regulate As2O3-induced apoptosis though caspase cascade. Furthermore, JNK1 siRNA abrogated As2O3-induced JNK2 phosphorylation and JNK2 siRNA abrogated As2O3-induced JNK1 phosphorylation, suggesting that JNK1 and JNK2 interact with each other. Moreover, JNK1 siRNA, but not JNK2 siRNA, abrogated As2O3-induced ERK1/2 phosphorylation. JNK2 siRNA together with PD98059, a specific MAPK/ERK kinase inhibitor, suppressed As2O3-induced apoptosis more significantly than JNK2 siRNA alone. These results indicated that As2O3 induces apoptosis of NCI-H2052 cells mainly through JNK1/2 activation, and that ERK1/2 is involved in As2O3-induced apoptosis when JNK1/2 are inactivated.

Copyright © 2010 Wiley-Liss, Inc.

In plain English

This was a laboratory study of one human mesothelioma cell line, NCI-H2052, grown in dishes. No patients or animals were involved, and asbestos was not studied. The authors, from Hyogo College of Medicine and the University of Shizuoka in Japan, treated the cells with arsenic trioxide, a drug used to treat acute promyelocytic leukemia. Arsenic trioxide reduced the number of living cells. The concentration that cut viability by half fell within the range the authors said is used clinically. The drug significantly increased the proportion of cells undergoing apoptosis (programmed cell death). It activated an enzyme called caspase-3 and two groups of signaling proteins, JNK1/2 and ERK1/2, but not p38. Blocking caspases reduced cell death significantly but not entirely. Lowering JNK1 or JNK2 levels with small interfering RNAs reduced caspase-3 activation and cell death, and lowering JNK1 had the greater effect. Lowering JNK1, but not JNK2, also markedly reduced ERK1/2 activation. The authors concluded that arsenic trioxide induces apoptosis in these mesothelioma cells mainly through JNK1/2 and caspase-3, and that ERK1/2 is involved when JNK1/2 are inactivated.

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) cell culture experiment
• Who was studied: one human mesothelioma cell line, NCI-H2052, obtained from the American Type Culture Collection; no human subjects or animals
• Exposure: Arsenic trioxide (As2O3), a drug, was applied to the cells for 2 to 72 hours. It was given alone or together with a caspase inhibitor (zVAD), an ERK pathway inhibitor (PD98059), or small interfering RNAs that lower the levels of JNK1 or JNK2. Asbestos exposure was not studied.
• Main results:
  • Arsenic trioxide suppressed viability of NCI-H2052 cells. The IC50 (the concentration that cuts viability by half) is printed as 5 mM. The authors said this falls within the clinically used range, printed as 1 to 10 mM.
  • Arsenic trioxide significantly increased the proportion of early apoptotic cells and of late apoptotic and necrotic cells among NCI-H2052 cells.
  • The caspase inhibitor zVAD blocked the increase in apoptotic cells significantly but not entirely.
  • ERK1/2 and JNK1/2, but not p38, were markedly activated (phosphorylated) 24 hours after arsenic trioxide treatment.
  • Lowering JNK1 or JNK2 levels with siRNA suppressed arsenic trioxide-induced apoptosis. JNK1 siRNA had the greater suppressive effect.
  • Arsenic trioxide-induced ERK1/2 activation was markedly abrogated by JNK1 siRNA but not by JNK2 siRNA.
  • JNK2 siRNA combined with the ERK pathway inhibitor PD98059 suppressed arsenic trioxide-induced apoptosis more significantly than JNK2 siRNA alone.
• The authors' conclusion: The authors concluded that arsenic trioxide activates JNK1 and JNK2, which in turn activate caspase-3 and JNK1-regulated ERK1/2, leading to apoptosis in human mesothelioma cells.
• Limitations the authors state:
  • Initial experiments with chemical JNK inhibitors gave inconsistent results, so the authors used siRNA knockdown instead.
  • The authors stated that the mechanism of ERK1/2 involvement needs further investigation.

Topics

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

Medical terms in this study, explained in our Lexicon: Apoptosis, Mesothelioma, Malignant Mesothelioma, Serosal Surface, Stomach Cancer.

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