Mesothelioma cells escape heat stress by upregulating Hsp40/Hsp70 expression via mitogen-activated protein kinases

Our plain-English summary of Mesothelioma cells escape heat stress by upregulating Hsp40/Hsp70 expression via mitogen-activated protein kinases, by M. Roth, J. Zhong, M. Tamm, et al (Journal of Biomedicine & Biotechnology, 2009).

The study

• Authors: M. Roth, J. Zhong, M. Tamm, J. Szilard
• Journal: Journal of Biomedicine & Biotechnology
• Published: 2009;2009:451084
• Cited by: 16 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Therapy with hyperthermal chemotherapy in pleural diffuse malignant mesothelioma had limited benefits for patients. Here we investigated the effect of heat stress on heat shock proteins (HSP), which rescue tumour cells from apoptosis. In human mesothelioma and mesothelial cells heat stress (39-42 degrees C) induced the phosphorylation of two mitogen activated kinases (MAPK) Erk1/2 and p38, and increased Hsp40, and Hsp70 expression. Mesothelioma cells expressed more Hsp40 and were less sensitive to heat stress compared to mesothelial cells. Inhibition of Erk1/2 MAPK by PD98059 or by Erk1 siRNA down-regulated heat stress-induced Hsp40 and Hsp70 expression and reduced mesothelioma cell survival. Inhibition of p38MAPK by SB203580 or siRNA reduced Hsp40, but not Hsp70, expression and also increased mesothelioma cell death. Thus hyperthermia combined with suppression of p38 MAPK or Hsp40 may represent a novel approach to improve mesothelioma therapy.

In plain English

This was a laboratory study of cells grown in dishes, not of patients. The authors used three human cell lines from pleural diffuse malignant mesothelioma and one non-cancerous mesothelial cell line (Met5, immortalised with the virus SV40). They heated the cells in a water bath at 37 to 42 degrees C for up to 30 minutes. Some cells were first treated with drugs or small inhibitory RNAs that block two signalling proteins (Erk1/2 and p38 MAPK) or two heat shock proteins (Hsp40 and Hsp70). Asbestos was not tested; it appears only as background. Heating at 41 degrees C for 10 minutes significantly reduced growth of the mesothelioma cells, but the non-cancerous cells were significantly more sensitive to heat. Heat raised Hsp70 in both cell types and strongly raised Hsp40 in the mesothelioma cells. Blocking Erk1 or p38, or reducing Hsp40, made mesothelioma cells more sensitive to heat. Reducing Hsp70 had a much smaller effect. The authors concluded that inhibiting Hsp40/Hsp70 or Erk1/2 might offer a new option to improve heat treatment of mesothelioma. Parts of the article describe the effects of blocking Erk1/2 and p38 inconsistently.

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 cell-culture experiment (in vitro)
• Who was studied: Three human pleural diffuse malignant mesothelioma (PDMM) cell lines and one SV40-immortalised human mesothelial cell line (Met5) used as a control. No patients were studied.
• Exposure: Heat stress, not asbestos. Cells were placed in a water bath at 37 to 42 degrees C for 0, 5, 10, 20 or 30 minutes. In some experiments the cells were first treated with the Erk1/2 inhibitor PD98059 (10 μM), the p38 inhibitor SB203580 (10 μM), or small inhibitory RNAs against Erk1, p38, Hsp40 or Hsp70.
• Main results:
  • In the mesothelioma cells, heat stress (41 degrees C, 10 minutes) significantly reduced proliferation after 3 days (P less than .01).
  • The non-malignant mesothelial cells were significantly more sensitive to rising temperature than the mesothelioma cells. In mesothelial cells, a rise above 39 degrees C for 20 minutes significantly reduced proliferation (P less than .01).
  • p38 MAPK was constantly active in the mesothelioma cells, and heat did not change this. In mesothelial cells, temperatures above 40 degrees C activated p38 within 10 minutes.
  • In mesothelial cells, heat above 40 degrees C increased Hsp70 within 24 hours.
  • In mesothelioma cells, heat stress (40 degrees C, 20 minutes) increased Hsp70 from 6 hours onward.
  • Unlike in mesothelial cells, Hsp40 was strongly increased by heat stress (40 degrees C, 20 minutes) in mesothelioma cells at 24 and 48 hours.
  • In mesothelioma cells, blocking Erk1/2 (with PD98059 or Erk1 siRNA) partly reduced Hsp70 and fully reduced Hsp40.
  • According to the results section, blocking p38 MAPK in mesothelioma cells reduced heat-induced Hsp70 and reduced Hsp40 to a lesser degree. The abstract describes the opposite pattern.
  • Pre-treatment with p38 or Erk1 siRNA increased the heat sensitivity of mesothelioma cells, with significantly lower cell counts after 3 days.
  • In mesothelioma cells, reducing Hsp40 with siRNA did not change basic growth but significantly increased sensitivity to heat stress.
  • In mesothelioma cells, reducing Hsp70 with siRNA also increased heat sensitivity, but much less than reducing Hsp40.
  • Caspase-3, used as a marker of programmed cell death, rose only slightly in heat-stressed mesothelioma cells, and the rise did not track with temperature.
• The authors' conclusion: The authors concluded that mesothelioma cells respond to heat by making more Hsp40 and Hsp70, which rescue them from death. They suggested that inhibiting Hsp40/Hsp70 or Erk1/2 MAPK might present a new option to increase the success of hyperthermia in mesothelioma.

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, Chemotherapy, Apoptosis, Mesothelial Cells.

Related studies

• Rat mesothelioma cell proliferation requires p38δ mitogen activated protein kinase and C/EBP-α — J. Zhong, D. Lardinois, et al. (2011)
• Quercetin and Cisplatin combined treatment altered cell cycle and mitogen activated protein kinase expressions in malignant mesotelioma cells — A. Demiroglu-Zergeroglu, E. Ergene, et al. (2016)
• Mitogen-activated protein kinase expression and activation does not differentiate benign from malignant mesothelial cells — L. Vintman, S. Nielsen, et al. (2005)
• Fibroblast growth factor-10 prevents asbestos-induced alveolar epithelial cell apoptosis by a mitogen-activated protein kinase-dependent mechanism — D. Upadhyay, V. Panduri, et al. (2005)
• Oxidants and signaling by mitogen-activated protein kinases in lung epithelium — B.T. Mossman, K.M. Lounsbury, et al. (2006)
• Persistent localization of activated extracellular signal-regulated kinases (ERK1/2) is epithelial cell-specific in an inhalation model of asbestosis — A.B. Cummins, C. Palmer, et al. (2003)

Browse more research in Journal of Biomedicine & Biotechnology, or return to medical research.