Int J Cancer. 2013 Apr 18. doi: 10.1002/ijc.28218. [Epub ahead of print]
Calretinin is essential for mesothelioma cell growth/survival in vitro: A potential new target for malignantmesothelioma therapy?
Source
Anatomy, Department of Medicine, University of Fribourg, Route Albert-Gockel 1, CH-1700 Fribourg, Switzerland.
Abstract
Malignant mesothelioma (MM) are highly aggressive asbestos-related neoplasms, which show strong chemotherapy-resistance and there is no effective cure for MM so far. Calretinin (CR) is widely used as a diagnostic marker for epithelioid and mixed (biphasic) mesothelioma, but still little is known about CR's putative function(s) in tumorigenesis. CR protects against asbestos-induced acute cytotoxicity mediated by the AKT/PI3K pathway and furthermore, SV40 early region genes are able to up-regulate CR in mesothelial cells. However, the precise role of CR in mesothelioma is still unknown. Down-regulation of CR via lentiviral-mediated shRNA significantly decreased the viability and proliferation of mesothelioma cells in vitro. The effect was strong in epithelioid-dominated cell lines (ZL55, MSTO-211H). A weaker and delayed effect was observed in mesothelioma cells with prevalent sarcomatoid morphology (SPC111, SPC212, ZL34). The specificity of the effect was confirmed by stable eGFP-CR expression inmesothelioma cell lines and subsequent down-regulation. Depletion of CR led these cancer cell lines to enter apoptosis within 72h post-infection via strong activation of the intrinsic caspase 9-dependent pathway. Down-regulation of CR in immortalized mesothelial cells LP9/TERT-1 strongly blocked proliferation and caused a G1 block without decreasing viability or activating apoptosis pathways. Our results demonstrate that down-regulation of CR had a strong effect on the viability of MM cells and that CR is essential for cells derived from malignant mesothelioma. We anticipate these findings to reveal calretinin as a highly interesting new putative therapeutic target for mesothelioma treatment of especially the epithelioid, but also of the mixed and sarcomatoid type.
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