Abstract
Malignant mesothelioma (MM) is an aggressive asbestos-linked neoplasm, characterized by dysregulation of signaling pathways. Due to intrinsic or acquired chemoresistance, MM treatment options remain limited. Calretinin is a Ca2+-binding protein expressed during MM tumorigenesis that activates the FAK signaling pathway, promoting invasion and epithelial-to-mesenchymal transition. Constitutive calretinin downregulation decreases MM cells’ growth and survival, and impairs tumor formation in vivo. In order to evaluate early molecular events occurring during calretinin downregulation, we generated a tightly controlled IPTG-inducible expression system to modulate calretinin levels in vitro. Calretinin downregulation significantly reduced viability and proliferation of MM cells, attenuated FAK signaling and reduced the invasive phenotype of surviving cells. Importantly, surviving cells showed a higher resistance to cisplatin due to increased Wnt signaling. This resistance was abrogated by the Wnt signaling pathway inhibitor 3289-8625. In various MM cell lines and regardless of calretinin expression levels, blocking of FAK signaling activated the Wnt signaling pathway and vice versa. Thus, blocking both pathways had the strongest impact on MM cell proliferation and survival. Chemoresistance mechanisms in MM cells have resulted in a failure of single-agent therapies. Targeting of multiple components of key signaling pathways, including Wnt signaling, might be the future method-of-choice to treat MM.
Highlights
Malignant mesothelioma (MM) is an aggressive cancer that arises from mesothelial cells covering the surfaces of the pleura, peritoneum, and pericardium, and is typically associated with exposure to asbestos fibers [1]
Calretinin is a Ca2+-binding protein expressed during MM tumorigenesis that activates the focal adhesion kinase (FAK) signaling pathway, promoting invasion and epithelial-to-mesenchymal transition
MSTO-211H cells, a commonly used MM cell line for in vitro and in vivo studies, were initially transduced with a lentivirus leading to the constitutive expression of TurboGFP
Summary
Malignant mesothelioma (MM) is an aggressive cancer that arises from mesothelial cells covering the surfaces of the pleura, peritoneum, and pericardium, and is typically associated with exposure to asbestos fibers [1]. A multimodal treatment regimen of chemotherapy consisting in cisplatin (Cis-Pt) plus pemetrexed, surgery, and radiotherapy provide the best long-term results [4]. Even after such an aggressive approach, the median overall survival time is less than 12 months [5]. With the possibility of massively parallel sequencing strategies, a more genome-wide view on the genetic landscape of MM is slowly emerging [6] This is expected to lead to the identification of several altered genes and signaling pathways that might serve to identify potential novel candidates for specific MM-targeted approaches [7]
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