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

Abstract

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.

High prevalence of serum antibodies reacting with simian virus 40 capsid protein mimotopes in patients affected by malignant pleural mesothelioma

“…Contrasting reports have appeared in the literature on the presence of SV40 footprints in humans and its association with human tumors (20)(21)(22). SV40 antibody detection had been attempted in several studies using serologic methods with SV40 virus-like particles (VLPs), but because of high protein homology among the three main polyomaviruses SV40, BKV, and JCV, the results were always affected by some cross-reactivity (23)(24)(25)(26)(27)(28)(29)(30).…”

A bipartite butyrate‐responsive element in the human calretinin (CALB2) promoter acts as a repressor in colon carcinoma cells but not in mesothelioma cells

“…Mutations in either BRE 5 or BRE 6 reduced the repressor effect by approximately 50% each indicating that both elements contribute to the butyrate-induced repression of CR expression. Since aberrant expression of CR is also the hallmark of mesotheliomas, in particular of the epithelial type, we used either the SV40-immortalized cell line MeT-5A or the mesothelioma cell line ZL34 that both express CR [Henzi et al, 2009] and [Saydan et al, 2001], respectively. Unlike in colon cancer cells, where butyrate mainly affects proliferation, doses of >1 mM led to massive death of cells of mesothelial origin starting from the third day of butyrate treatment.…”

Pathophysiology and biology of peritoneal carcinomatosis

“…The question as to whether the SV40 virus is involved as a possible cofactor is still highly debated. Henzi et al [41] have shown 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 contributes significantly to this protective effect because cells stably transfected with calretinin cDNA were shown to be more resistant to the toxic effects of crocidolite than mock-transfected control cells.…”