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Originally published online as doi:10.2353/ajpath.2009.080352 on May 12, 2009

Published online before print May 12, 2009
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(American Journal of Pathology. 2009;174:2324-2336.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080352

SV40-Induced Expression of Calretinin Protects Mesothelial Cells from Asbestos Cytotoxicity and May Be a Key Factor Contributing to Mesothelioma Pathogenesis

Thomas Henzi*, Walter-Vincent Blum*, Martine Pfefferli*, Tadeusz J. Kawecki{dagger}, Valerie Salicio* and Beat Schwaller*

From the Department of Medicine,* Unit of Anatomy, University of Fribourg, Fribourg; and the Department of Ecology and Evolution,{dagger} University of Lausanne, Lausanne, Switzerland

The calcium-binding protein calretinin has emerged as a useful marker for the identification of mesotheliomas of the epithelioid and mixed types, but its putative role in tumor development has not been addressed previously. Although exposure to asbestos fibers is considered the main cause of mesothelioma, undoubtedly, not all mesothelioma patients have a history of asbestos exposure. The question as to whether the SV40 virus is involved as a possible co-factor is still highly debated. Here we show that increased expression of SV40 early gene products in the mesothelial cell line MeT-5A induces the expression of calretinin and that elevated calretinin levels strongly correlate with increased resistance to asbestos cytotoxicity. Calretinin alone mediates a significant part of this protective effect because cells stably transfected with calretinin cDNA were clearly more resistant to the toxic effects of crocidolite than mock-transfected control cells. Down-regulation of calretinin by antisense methods restored the sensitivity to asbestos toxicity to a large degree. The protective effect observed in clones with higher calretinin expression levels could be eliminated by phosphatidylinositol 3-kinase (PI3K) inhibitors, implying an important role for the PI3K/AKT signaling (survival) pathway in mediating the protective effect. Up-regulation of calretinin, resulting from either asbestos exposure or SV40 oncoproteins, may be a common denominator that leads to increased resistance to asbestos cytotoxicity and thereby contributes to mesothelioma carcinogenesis.






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Copyright © 2009 by the American Society for Investigative Pathology.