Mesothelioma Cells Escape Heat Stress by Upregulating Hsp40/Hsp70 Expression via Mitogen‐Activated Protein Kinases

Michael Roth,Michael Tamm,John Szilard,Jun Zhong

doi:10.1155/2009/451084

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°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.

Highlights

Pleural Diffuse Malignant Mesothelioma (PDMM) is mainly induced by inhalation of asbestos crystals, or to a lesser extent by SV40 infection [1]
As we reported earlier p38 mitogen activated protein kinases (MAPK) was constitutively activated in PDMM cells [15] and heat stress did not modify this effect (Figure 2(a))
This study provides evidence that mesothelial cells produce less Hsp40 than PDMM cells and are more sensitive to heat stress than PDMM cells

Summary

Introduction

Pleural Diffuse Malignant Mesothelioma (PDMM) is mainly induced by inhalation of asbestos crystals, or to a lesser extent by SV40 infection [1]. Normal mesothelial cells enable the pleural sheets of the rib cage and the lung to move freely This function is hindered by asbestos fibres which induce a local inflammation of the pleura which is linked to the activation of intra cellular signalling proteins such as mitogen activated protein kinases (MAPK) and subsequent transcription factors. Amphiboles and crionite induce, the malignant transformation of mesothelial cells by a mechanism that leads to a constitutive activation of intracellular signal transduction regulators including different MAPK and adhesion molecules [6, 7]. The observation that mesothelial cell proliferation is controlled by intracellular signalling proteins, mainly the MAPK Erk1/2 and p38 is of interest as both are activated by asbestos and by oxidative stress [11,12,13,14,15]. Asbestos constitutively activates p38 MAPK in PDMM cells [14,15,16], the underlying mechanism and its contribution to PDMM cell proliferation is unclear

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Conclusion