Hedgehog pathway inhibitor-4 suppresses malignant properties of chondrosarcoma cells by disturbing tumor ciliogenesis

Abstract

Chondrosarcoma is a type of malignant bone tumor secreting cartilage-like matrix. In clinical treatment, there is no frequently used drug treatment option except for surgical resection. Hedgehog (HH) pathway is a classical signaling pathway that regulates normal cartilage cell development. In order to detect the role that HH pathway plays in chondrosarcoma, we used immunohistochemistry and found this tumor clearly expressed HH pathway-related proteins. Treatment with HH pathway inhibitor-4 (HPI-4) could significantly decrease human chondrosarcoma cell proliferation, invasion and migration ability. Furthermore, HPI-4 could distinctly disturb HH pathway-mediated ciliogenesis and suppress primary cilia-related protein intraflagellar transport protein IFT88 expression. HH downstream effect molecular GLI2 was restrained to block parathyroid hormone-related protein and affect MAPK/ERK-regulated matrix metalloproteinases (MMP2 and MMP9). These results indicated that activated HH pathway existed in chondrosarcoma and HPI-4 could be a new therapeutic option specific to chondrosarcoma expressing elevated levels of HH pathway.

Targeting GLI factors to inhibit the Hedgehog pathway

“…In contrast, HPI-2 and HPI-3 have been associated with an altered trafficking of GLI1 and with increased stability of GLI2, which in turn impairs the conversion of full-length GLI2 to a transcriptional activator. Finally, HPI-4 has been found to perturb ciliogenesis by an unclear mechanism, and to decrease human chondrosarcoma cell proliferation, invasion, and migration [102]. Only HPI-1 and HPI-4 have been shown to inhibit the proliferation of Glabrescione B (GlaB) Natural products have historically had a significant impact in Hh modulation (i.e., cyclopamine).…”

The primary cilium as a signaling nexus for growth plate function and subsequent skeletal development

“…However, this mutation also results in a loss of Gli3 , which is known to restore PTHrP expression. Treatment with Hh pathway inhibitor 4 (HPI‐4) decreases both Ift88 and PTHrP protein and mRNA expression . Additionally, Ift88 expression and cilium incidence increase when the PTHrP gene is silenced .…”

The Fungal Metabolite Brefeldin A Inhibits Dvl2-Plk1-Dependent Primary Cilium Disassembly

“…Although the underlying mechanism of how those events are regulated remains unclear, the importance of the regulation of primary cilia for treating ciliopathy and cancer has recently emerged (Peluso et al, 2014; Xiang et al, 2014). Therefore, primary cilium regulation-based drug development is just the beginning.…”