PDF(Pubmed)
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.
摘要：
ADP-核糖基化因子样蛋白13B(ARL13B),调节GTP酶和鸟嘌呤交换因子(GEF)，富集初级纤毛并部分通过调节平滑（SMO）促进肿瘤发生，GLI,和SonicHedgehog（SHH）信号。伴有ARL13B增加的胶质瘤，SMO,GLI2表达更具侵略性，但与纤毛的关系尚不清楚。先前的研究表明，胶质母细胞瘤细胞中ARL13B的增加促进了纤毛SMO的积累，与外源SHH的添加无关。这里,我们发现SMO积累是由于纤毛增加，但不是纤毛，ARL13B.增加ARL13B表达促进神经胶质瘤纤毛中激活的SMO和GLI2的积累。ARL13B驱动的纤毛SMO和GLI2的增加对SMO抑制剂具有抗性，GDC-0449和环巴胺。令人惊讶的是,ARL13B诱导的纤毛SMO/GLI2变化与下游SHH途径基因的规范变化无关。然而,神经胶质瘤细胞系，其纤毛过表达WT但不表达鸟嘌呤交换因子缺陷的ARL13B，显示减少INPP5e，一种睫状膜成分，其消耗可能有利于SMO/GLI2富集。过表达ARL13B的神经胶质瘤细胞也显示纤毛骨内转运88（IFT88）减少，提示逆行转运的改变可以进一步促进SMO/GLI的积累。总的来说，我们的数据表明，增加神经胶质瘤细胞中ARL13B表达的因素可能促进睫状膜特征和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研究。
