TY - JOUR
T1 - SV40-dependent AKT activity drives mesothelial cell transformation after asbestos exposure
AU - Cacciotti, Paola
AU - Barbone, Dario
AU - Porta, Camillo
AU - Altomare, Deborah A.
AU - Testa, Joseph R.
AU - Mutti, Luciano
AU - Gaudino, Giovanni
PY - 2005/6/15
Y1 - 2005/6/15
N2 - 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.
AB - 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.
KW - Apoptosis/physiology
KW - Asbestos/toxicity
KW - Cell Transformation, Viral
KW - Cocarcinogenesis
KW - Epithelial Cells/cytology
KW - Humans
KW - Mesothelioma/enzymology
KW - Phosphatidylinositol 3-Kinases/metabolism
KW - Phosphorylation
KW - Protein Serine-Threonine Kinases/metabolism
KW - Proto-Oncogene Proteins c-akt
KW - Proto-Oncogene Proteins/metabolism
KW - Simian virus 40/physiology
UR - http://www.scopus.com/inward/record.url?scp=20444480256&partnerID=8YFLogxK
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=purepublist2023&SrcAuth=WosAPI&KeyUT=WOS:000229734300038&DestLinkType=FullRecord&DestApp=WOS
U2 - 10.1158/0008-5472.CAN-05-0127
DO - 10.1158/0008-5472.CAN-05-0127
M3 - Article
C2 - 15958571
SN - 0008-5472
VL - 65
SP - 5256
EP - 5262
JO - Cancer Research
JF - Cancer Research
IS - 12
ER -