SV40-dependent AKT activity drives mesothelial cell transformation after asbestos exposure.

Abstract

Human malignant mesothelioma is an aggressive cancer generally associated with exposure to asbestos, although SV40 virus has been involved as a possible cofactor by a number of studies. Asbestos fibers induce cytotoxicity in human mesothelial cells (HMC), although cell survival activated by key signaling pathways may promote transformation. We and others previously reported that SV40 large T antigen induces autocrine loops in HMC and malignant mesothelioma cells, leading to activation of growth factor receptors. Now we show that SV40 induces cell survival via Akt activation in malignant mesothelioma and HMC cells exposed to asbestos. Consequently, prolonged exposure to asbestos fibers progressively induces transformation of SV40-positive HMC. As a model of SV40/asbestos cocarcinogenesis, we propose that malignant mesothelioma originates from a subpopulation of transformed stem cells and that Akt signaling is a novel therapeutic target to overcome malignant mesothelioma resistance to conventional therapies.

• Authors: Paola Cacciotti, Dario Barbone, Camillo Porta, Deborah A Altomare, Joseph R Testa, Luciano Mutti, Giovanni Gaudino
• Journal: Cancer research (Cancer Res) Vol. 65 Issue 12 Pg. 5256-62 (Jun 15 2005) ISSN: 0008-5472 [Print] United States
• PMID: 15958571 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Proto-Oncogene Proteins
• Asbestos
• AKT1 protein, human
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt

Topics

• Apoptosis (physiology)
• Asbestos (toxicity)
• Cell Transformation, Viral
• Cocarcinogenesis
• Epithelial Cells (cytology, drug effects, enzymology, virology)
• Humans
• Mesothelioma (enzymology, etiology, pathology, virology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation
• Protein Serine-Threonine Kinases (metabolism)
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-akt
• Simian virus 40 (physiology)