Abstract
Primary cilium drives the left-right asymmetry process during embryonic development. Moreover, its dysregulation contributes to cancer progression by affecting various signaling pathways. The fibroblast growth factor (FGF)/FGF receptor (FGFR) system modulates primary cilium length and plays a pivotal role in embryogenesis and tumor growth. Here, we investigated the impact of the natural FGF trap long-pentraxin 3 (PTX3) on the determination of primary cilium extension in zebrafish embryo and cancer cells. The results demonstrate that down modulation of the PTX3 orthologue ptx3b causes the shortening of primary cilium in zebrafish embryo in a FGF-dependent manner, leading to defects in the left-right asymmetry determination. Conversely, PTX3 upregulation causes the elongation of primary cilium in FGF-dependent cancer cells. Previous observations have identified the PTX3-derived small molecule NSC12 as an orally available FGF trap with anticancer effects on FGF-dependent tumors. In keeping with the non-redundant role of the FGF/FGR system in primary cilium length determination, NSC12 induces the elongation of primary cilium in FGF-dependent tumor cells, thus acting as a ciliogenic anticancer molecule in vitro and in vivo. Together, these findings demonstrate the ability of the natural FGF trap PTX3 to exert a modulatory effect on primary cilium in embryonic development and cancer. Moreover, they set the basis for the design of novel ciliogenic drugs with potential implications for the therapy of FGF-dependent tumors.
Highlights
Primary cilia are antenna-like organelles protruding from most mammalian cells [1] to act as chemosensors and mechanosensors for external stimuli [2]
Primary cilia in the embryonic node are involved in the left-right asymmetry process [7] and genetic defects in primary cilia are associated with a variety of pathological conditions that are grouped under the name “ciliopathies”
We investigated the effect of the modulation of pentraxin 3 (PTX3) expression on primary cilium extension in zebrafish embryo and cancer cells
Summary
Primary cilia are antenna-like organelles protruding from most mammalian cells [1] to act as chemosensors and mechanosensors for external stimuli [2]. Primary cilia in the embryonic node are involved in the left-right asymmetry process [7] and genetic defects in primary cilia are associated with a variety of pathological conditions that are grouped under the name “ciliopathies” (reviewed in [8,9,10]). Due to their role in the modulation of various signaling pathways, including Hedgehog (Hh) and Wnt, dysregulation of primary cilia plays an important role in cancer progression [11,12,13]
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