Rat mesothelioma cell proliferation requires p38δ mitogen activated protein kinase and C/EBP-α

Our plain-English summary of Rat mesothelioma cell proliferation requires p38δ mitogen activated protein kinase and C/EBP-α, by J. Zhong, D. Lardinois, J. Szilard, et al (Lung Cancer, 2011).

The study

• Authors: J. Zhong, D. Lardinois, J. Szilard, M. Tamm, M. Roth
• Journal: Lung Cancer
• Published: 2011;73(2):166-70
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Pleural malignant mesothelioma is a rare but deadly tumour mainly induced by asbestos inhalation. Despite the ban of asbestos in 1990 in 52 countries, mesothelioma cases still increase worldwide. In pleural mesothelioma, p38 mitogen activated protein kinases (MAPK) have been suggested to play a major role in carcinogenesis and aggressiveness of tumours. The aim of this study was to determine the role of the different four p38 MAPK isoforms and their effect on proliferation together with the underlying signalling pathways in a rat pleural mesothelioma cell line. Rat pleural mesothelioma cells were stimulated with platelet-derived growth factor (PDGF)-BB and/or transforming growth factor beta (TGF)-β. MAPK and transcription factor expression and activation was monitored in the cytosol and nucleus by immuno-blotting. Proliferation was determined by manual cell count and siRNAs were used to control MAPK and transcription factor expression and action. Only PDGF-BB, but not TGF-β1 induced proliferation via activated Erk1/2 and p38 MAPK. The p38α and δ isoforms were expressed in the cytosol, and upon activation p38δ translocated into the nucleus, while p38α remained in the cytosol. No other p38 isoform was expressed by rat mesothelioma cells. C/EBP-α was found in both the cytosol and the nucleus, while C/EBP-β was not expressed at all. PDGF-BB induced proliferation was suppressed by down-regulation of either Erk1/2, or p38δ MAPK, or C/EBP-α. Furthermore, TGF-β inhibited PDGF-BB induced proliferation by interruption of p38 MAPK signalling. From this rat model, we conclude that in pleural mesothelioma, p38δ in C/EBP-α mediate proliferation and thus may represent new targets in mesothelioma therapy.

Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

In plain English

This was a laboratory study of cells, not of people or live animals. The authors grew a mesothelioma cell line (II-45) from Fischer 344 rats exposed to asbestos. The article does not name the fiber type. They treated the cells with the growth factors PDGF-BB and TGF-β, tracked p38 kinases and C/EBP proteins, and counted the cells after 48 hours. PDGF-BB increased cell growth, and more PDGF-BB gave more growth. TGF-β alone did not increase growth, and adding TGF-β abolished the effect of PDGF-BB. Chemical blockers showed that growth driven by PDGF-BB depended on two kinases, Erk1/2 and p38. The authors looked at all four known p38 forms and used siRNAs to reduce the two they judged relevant, α and δ. Only reducing p38δ significantly lowered that growth. Of the two C/EBP proteins tested, α and β, only C/EBP-α was involved in controlling growth. After activation, p38δ moved into the cell nucleus within 30 minutes. The authors concluded that this p38δ and C/EBP-α link might be a new mechanism in how mesothelioma develops, and that these proteins may be new therapy targets.

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 using a single rat mesothelioma cell line
• Who was studied: One established rat pleural mesothelioma cell line (II-45), derived from Fischer 344 rats exposed to asbestos and obtained from the Research Laboratory, UT MD Anderson Cancer Center, Smithville, TX. The article gives no human subjects and no study dates.
• Exposure: The cells came from asbestos-exposed rats, but the article does not name a fiber type or dose. In the experiments the cells were not exposed to asbestos. They were stimulated with fetal calf serum (0.5–10%), PDGF-BB (0.1–20 ng/ml) and TGF-β (0.1–10 ng/ml). Specific proteins were blocked with siRNAs and with chemical inhibitors (PD98059, SB203580).
• Main results:
  • In six independent experiments, PDGF-BB stimulated rat mesothelioma cell proliferation in a dose-dependent manner, while TGF-β alone did not.
  • When PDGF-BB and TGF-β were combined (n = 6), TGF-β abolished the stimulatory effect of PDGF-BB in a dose-dependent pattern.
  • With chemical inhibitors, PDGF-BB-induced proliferation was dependent on Erk1/2 and p38 MAPK, in 24 independent experiments for each condition.
  • The authors examined the four known p38 isoforms. They then used siRNAs to reduce the two isoforms they called relevant (α and δ, per the PubMed abstract), and only the siRNA targeting p38δ significantly reduced PDGF-BB-induced proliferation. The article's abstract states that PDGF-BB-induced proliferation was also suppressed by down-regulating Erk1/2 or C/EBP-α.
  • In six independent experiments with siRNAs for the two C/EBP proteins tested (C/EBP-α and C/EBP-β), only C/EBP-α was involved in proliferation control. The isoform names come from the PubMed abstract.
  • After stimulation, p38δ (per the PubMed abstract) was found in the cytosol and moved into the nucleus within 30 minutes, reaching maximal accumulation at 3 hours.
  • In six independent experiments, more activated Erk1/2 MAPK was found in the nucleus of the rat mesothelioma cells than in the cytosol.
• The authors' conclusion: The authors concluded that the link they observed between p38δ moving into the nucleus and the role of C/EBP-α in mesothelioma cell proliferation might be a novel pathology underlying the malignant transformation of mesothelial cells into mesothelioma. In the abstract they added that these may represent new targets in mesothelioma therapy.

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelioma, Malignant Mesothelioma, Pleural Mesothelioma, Carcinogenesis, Platelet-Derived Growth Factor (PDGF).

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