Anatomy, Section of Medicine, University of Fribourg, Route Albert-Gockel 1, 1700 Fribourg, Switzerland.
Genetica AG, 8001 Zurich, Switzerland.
Int J Mol Sci. 2019 Oct 29;20(21):5391. doi: 10.3390/ijms20215391.
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 Ca-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 . 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.
恶性间皮瘤（MM）是一种侵袭性的石棉相关肿瘤，其特征是信号通路失调。由于内在或获得性的化疗耐药性，MM 的治疗选择仍然有限。钙结合蛋白 calretinin 在 MM 肿瘤发生过程中表达，激活 FAK 信号通路，促进侵袭和上皮间质转化。calretinin 的组成性下调会降低 MM 细胞的生长和存活，并损害体内肿瘤的形成。为了评估 calretinin 下调过程中发生的早期分子事件，我们生成了一个严格控制的 IPTG 诱导表达系统，以体外调节 calretinin 水平。calretinin 的下调显著降低了 MM 细胞的活力和增殖，减弱了 FAK 信号，并降低了存活细胞的侵袭表型。重要的是，由于 Wnt 信号的增加，存活细胞对顺铂的耐药性增加。这种耐药性被 Wnt 信号通路抑制剂 3289-8625 所阻断。在各种 MM 细胞系中，无论 calretinin 的表达水平如何，阻断 FAK 信号都会激活 Wnt 信号通路。因此，阻断这两条通路对 MM 细胞的增殖和存活有最强的影响。MM 细胞中的化疗耐药机制导致单一药物治疗失败。针对关键信号通路的多个成分，包括 Wnt 信号通路，可能是治疗 MM 的未来首选方法。
