Increasing Ciliary ARL13B Expression Drives Active and Inhibitor-Resistant Smoothened and GLI into Glioma Primary Cilia.

Abstract

ADP-ribosylation factor-like protein 13B (ARL13B), a regulatory GTPase and guanine exchange factor (GEF), enriches in primary cilia and promotes tumorigenesis in part by regulating Smoothened (SMO), GLI, and Sonic Hedgehog (SHH) signaling. Gliomas with increased ARL13B, SMO, and GLI2 expression are more aggressive, but the relationship to cilia is unclear. Previous studies have showed that increasing ARL13B in glioblastoma cells promoted ciliary SMO accumulation, independent of exogenous SHH addition. Here, we show that SMO accumulation is due to increased ciliary, but not extraciliary, ARL13B. Increasing ARL13B expression promotes the accumulation of both activated SMO and GLI2 in glioma cilia. ARL13B-driven increases in ciliary SMO and GLI2 are resistant to SMO inhibitors, GDC-0449, and cyclopamine. Surprisingly, ARL13B-induced changes in ciliary SMO/GLI2 did not correlate with canonical changes in downstream SHH pathway genes. However, glioma cell lines whose cilia overexpress WT but not guanine exchange factor-deficient ARL13B, display reduced INPP5e, a ciliary membrane component whose depletion may favor SMO/GLI2 enrichment. Glioma cells overexpressing ARL13B also display reduced ciliary intraflagellar transport 88 (IFT88), suggesting that altered retrograde transport could further promote SMO/GLI accumulation. Collectively, our data suggest that factors increasing ARL13B expression in glioma cells may promote both changes in ciliary membrane characteristics and IFT proteins, leading to the accumulation of drug-resistant SMO and GLI. The downstream targets and consequences of these ciliary changes require further investigation.

• Authors: Ping Shi, Jia Tian, Julianne C Mallinger, Dahao Ling, Loic P Deleyrolle, Jeremy C McIntyre, Tamara Caspary, Joshua J Breunig, Matthew R Sarkisian
• Journal: Cells (Cells) Vol. 12 Issue 19 (09 26 2023) ISSN: 2073-4409 [Electronic] Switzerland
• PMID: 37830570 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Hedgehog Proteins
• phosphoinositide 5-phosphatase
• Phosphoric Monoester Hydrolases
• ARL13B protein, human
• Zinc Finger Protein Gli2
• Smoothened Receptor

Topics

• Humans
• Cilia (metabolism)
• Glioma (genetics, metabolism)
• Hedgehog Proteins (metabolism)
• Phosphoric Monoester Hydrolases (metabolism)
• Zinc Finger Protein Gli2 (metabolism)
• Smoothened Receptor (metabolism)