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Programmed necrosis induced by asbestos in human mesothelial cells causes high-mobility group box 1 protein release

Haining Yang1, Zeyana Rivera, Sandro Jube

  • 1Cancer Research Center of Hawaii, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96813, USA. hyang@crch.hawaii.edu

Proceedings of the National Academy of Sciences of the United States of America
|July 10, 2010
PubMed

Insights

Asbestos exposure causes human mesothelial cell death, releasing high-mobility group box 1 (HMGB1). This protein triggers inflammation and protects cells, promoting asbestos-related cancer development.

Area of Science:

  • Cell Biology
  • Toxicology
  • Cancer Research

Background:

  • Asbestos exposure is linked to cancer via inflammation and reactive oxygen species (ROS).
  • Asbestos cytotoxicity to human mesothelial cells (HM) seems paradoxical for a carcinogen.

Purpose of the Study:

  • To investigate the mechanism of asbestos-induced cell death in HM and its link to carcinogenesis.
  • To identify key molecular events connecting asbestos exposure, inflammation, and cancer development.

Main Methods:

  • Examined asbestos-induced cell death in HM, measuring poly(ADP-ribose) polymerase activation, H(2)O(2) secretion, ATP depletion, and high-mobility group box 1 protein (HMGB1) translocation.
  • Investigated HMGB1 and TNF-alpha expression in mesothelial and inflammatory cells in animal models exposed to asbestos.
  • Assessed HMGB1 levels in individuals exposed to asbestos versus controls.

Main Results:

  • Asbestos-induced HM cell death is a regulated necrosis.
  • HMGB1 translocates from the nucleus to the extracellular space, inducing macrophages to secrete TNF-alpha.
  • TNF-alpha protects HM from cell death but promotes chronic inflammation and transformation.
  • Elevated HMGB1 levels were observed in asbestos-exposed individuals.

Conclusions:

  • HMGB1 release is a critical initial step in asbestos-related disease pathogenesis.
  • Mechanistic links between asbestos-induced cell death, chronic inflammation, and carcinogenesis are established.
  • Targeting HMGB1 and the inflammatory response may offer chemopreventive strategies against malignant mesothelioma.

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