Increasing Ciliary ARL13B Expression Drives Active and Inhibitor-Resistant Smoothened and GLI into Glioma Primary Cilia.
Increasing Ciliary ARL13B Expression Drives Active and Inhibitor-Resistant Smoothened and GLI into Glioma Primary Cilia.
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ADP-核糖基化因子样蛋白13 B（ARL 13 B）是一种调节性GTP酶和鸟嘌呤交换因子（GEF），富含初级纤毛并部分通过调节Smoothened（SMO）、GLI和Sonic Hedgehog（SHH）信号传导促进肿瘤发生。ARL 13 B、SMO和GLI 2表达增加的胶质瘤更具侵袭性，但与纤毛的关系尚不清楚。先前的研究表明，增加胶质母细胞瘤细胞中的ARL 13 B促进睫状SMO积累，独立于外源性SHH添加。在这里，我们表明，SMO的积累是由于增加睫状体，而不是外睫状体，ARL 13 B。增加ARL 13 B表达促进胶质瘤纤毛中激活的SMO和GLI 2的积累。ARL 13 B驱动的睫状SMO和GLI 2的增加对SMO抑制剂GDC-0449和环巴胺具有抗性。令人惊讶的是，ARL 13 B诱导的睫状SMO/GLI 2的变化与下游SHH途径基因的典型变化无关。然而，其纤毛过表达WT但不表达鸟嘌呤交换因子缺陷型ARL 13 B的神经胶质瘤细胞系显示减少的INPP 5e，其消耗可能有利于SMO/GLI 2富集的睫状膜组分。过表达ARL 13 B的胶质瘤细胞也显示纤毛内鞭毛转运88（IFFT 88）减少，表明改变的逆行转运可进一步促进SMO/GLI积累。总的来说，我们的数据表明，在神经胶质瘤细胞中增加ARL 13 B表达的因素可能会促进睫状膜特征和IFT蛋白的变化，导致耐药SMO和GLI的积累。这些纤毛变化的下游目标和后果需要进一步调查。
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.
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DOI：
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发表时间：
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