Deficiency of Fyn protein is prerequisite for apoptosis induced by Src family kinase inhibitors in human mesothelioma cells

Our plain-English summary of Deficiency of Fyn protein is prerequisite for apoptosis induced by Src family kinase inhibitors in human mesothelioma cells, by R. Eguchi, S. Kubo, H. Takeda, et al (Carcinogenesis, 2012).

The study

• Authors: R. Eguchi, S. Kubo, H. Takeda, T. Ohta, C. Tabata, H. Ogawa, T. Nakano, Y. Fujimori
• Journal: Carcinogenesis
• Published: 2012;33(5):969-75
• Cited by: 20 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant mesothelioma is an aggressive tumor arising from mesothelial cells of serous membranes. Src family kinases (SFKs) have a pivotal role in cell adhesion, proliferation, survival and apoptosis. Here, we examined the effect of SFK inhibitors in NCI-H2052, ACC-MESO-4 and NCI-H28 cells, mesothelioma cell lines and Met5A, a human non-malignant mesothelial cell line. We found that PP2, a selective SFK inhibitor, inhibited SFK activity and induced apoptosis mediated by caspase-8 in NCI-H28 but not Met5A, NCI-H2052 and ACC-MESO-4 cells. Src, Yes, Fyn and Lyn protein, which are members of the SFK, were expressed in these cell lines, whereas NCI-H28 cells were deficient in Fyn protein. Small interfering RNA (siRNA) targeting Fyn facilitated PP2-induced apoptosis mediated by caspase-8 in NCI-H2052 and ACC-MESO-4 cells. PP2 reduced Lyn protein levels and suppressed SFK activity in all mesothelioma cell lines. Lyn siRNA induced caspase-8 activation and apoptosis in NCI-H28 cells but not in NCI-H2052 and ACC-MESO-4 cells. However, double RNA interference knockdown of Fyn and Lyn induced apoptosis accompanied by caspase-8 activation in NCI-H2052 and ACC-MESO-4 cells. Dasatinib, an inhibitor of multi-tyrosine kinases including SFK, also inhibited SFK activity and induced reduction of Lyn protein levels, caspase-8 activation and apoptosis in NCI-H28 cells but not in other cell lines. Present study suggests that SFK inhibitors induce caspase-8-dependent apoptosis caused by reduction of Lyn protein in Fyn-deficient mesothelioma cells.

In plain English

This laboratory study used human cells grown in dishes, not people, and did not examine asbestos. The authors tested two drugs that block Src family kinases, PP2 and dasatinib, on three human mesothelioma cell lines (NCI-H2052, ACC-MESO-4 and NCI-H28) and one non-malignant mesothelial cell line (Met5A). Both drugs reduced the viability of all three mesothelioma lines more than that of Met5A. Each drug significantly triggered apoptosis (programmed cell death) only in NCI-H28 cells. NCI-H28 was the only line lacking the protein Fyn. When the authors switched off Fyn in the other two mesothelioma lines, PP2 caused more apoptosis than in control-treated cells. PP2 lowered levels of another family member, Lyn. Switching off Lyn caused apoptosis in NCI-H28 cells, and switching off both Fyn and Lyn caused it in the other two lines. The authors concluded that lacking Fyn is a prerequisite for these drugs to cause apoptosis in mesothelioma cells. They said further study is needed of how Fyn and Lyn regulate cell death.

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) experiment on human cell lines
• Who was studied: Four human cell lines: three mesothelioma lines (NCI-H2052 and NCI-H28 from the American Type Culture Collection; ACC-MESO-4 from the RIKEN BioResource Center, Japan) and Met5A, a non-malignant transformed human pleural mesothelial cell line. Laboratory work was done at Hyogo College of Medicine, Japan. Data were from three independent experiments.
• Exposure: No asbestos exposure was studied. Cells were treated with the Src family kinase inhibitor PP2 and with dasatinib, an inhibitor of several tyrosine kinases including Src family kinases. Specific family members (Fyn, Lyn, Src, Yes) were also switched off using small interfering RNA.
• Main results:
  • PP2 significantly induced apoptosis in NCI-H28 cells but not in Met5A, NCI-H2052 or ACC-MESO-4 cells. This apoptosis in NCI-H28 cells was significantly suppressed by caspase inhibitors, including a specific caspase-8 inhibitor.
  • Src, Yes and Lyn proteins were found in all four cell lines, but NCI-H28 cells lacked Fyn protein, and their Fyn mRNA was much lower than in the other lines.
  • In NCI-H2052 and ACC-MESO-4 cells with Fyn switched off, PP2 induced apoptosis more significantly than in cells treated with control siRNA.
  • In NCI-H28 cells, PP2 reduced Lyn protein levels. This reduction was suppressed by the proteasome inhibitor MG132.
  • In NCI-H28 cells, switching off Src or Lyn, but not Yes, significantly induced apoptosis.
  • In NCI-H2052 and ACC-MESO-4 cells, switching off Src, Yes or Lyn individually failed to induce apoptosis. Switching off both Fyn and Lyn together induced significant apoptosis and caspase-8 and caspase-3 cleavage.
  • Dasatinib reduced viability of all mesothelioma lines more than Met5A. It significantly induced apoptosis only in NCI-H28 cells.
• The authors' conclusion: The authors concluded that PP2 and dasatinib reduce Lyn protein, leading to caspase-8-mediated apoptosis in Fyn-deficient mesothelioma cells, and that lack of Fyn protein is a prerequisite for this apoptosis. They suggested Fyn deficiency could be a biomarker of sensitivity to these drugs.
• Limitations the authors state:
  • The authors stated that how Fyn mRNA transcription is repressed in NCI-H28 cells still needs detailed investigation.
  • The authors stated that how Lyn and Fyn regulate apoptosis of mesothelioma cells 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, Mesothelial Cells.

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