Insights into the Regulation of Ciliary Disassembly

Patel, Maulin M.; Tsiokas, Leonidas

doi:10.3390/cells10112977

Cited by 23 publications

(18 citation statements)

References 119 publications

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“…24 Defective Rhodopsin trafficking is considered a common feature of RD in multiple ciliopathy models; moreover, in BBS animal models, endoplasmic reticulum stress response has been described. 25…”

Section: Retinal Dystrophymentioning

confidence: 99%

Bardet-Biedl Syndrome: Current Perspectives and Clinical Outlook

Melluso¹,

Secondulfo²,

Capolongo³

et al. 2023

TCRM

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The Bardet Biedl syndrome (BBS) is a rare inherited disorder considered a model of non-motile ciliopathy. It is in fact caused by mutations of genes encoding for proteins mainly localized to the base of the cilium. Clinical features of BBS patients are widely shared with patients suffering from other ciliopathies, especially autosomal recessive syndromic disorders; moreover, mutations in cilia-related genes can cause different clinical ciliopathy entities. Besides the best-known clinical features, as retinal degeneration, learning disabilities, polydactyly, obesity and renal defects, several additional clinical signs have been reported in BBS, expanding our understanding of the complexity of its clinical spectrum. The present review aims to describe the current knowledge of BBS i) pathophysiology, ii) clinical manifestations, highlighting both the most common and the less described features, iii) current and future perspective for treatment.

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Section: Retinal Dystrophymentioning

confidence: 99%

Bardet-Biedl Syndrome: Current Perspectives and Clinical Outlook

Melluso¹,

Secondulfo²,

Capolongo³

et al. 2023

TCRM

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“…This creates a protrusion, which ultimately becomes a cilium. As the cell reenters the cell cycle, the cilium will disassemble either through shedding or through axonemal disassembly before entering cell division (Patel & Tsiokas, 2021).…”

Section: Introduction Cell Division and Ciliogenesis Alternately Use ...mentioning

confidence: 99%

The ERK activator, BCI, inhibits ciliogenesis and causes defects in motor behavior, ciliary gating, and cytoskeletal rearrangement

2023

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MAPK pathways are well-known regulators of the cell cycle, but they have also been found to control ciliary length in a wide variety of organisms and cell types fromCaenorhabditis elegansneurons to mammalian photoreceptors through unknown mechanisms. ERK1/2 is a MAP kinase in human cells that is predominantly phosphorylated by MEK1/2 and dephosphorylated by the phosphatase DUSP6. We have found that the ERK1/2 activator/DUSP6 inhibitor, (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one (BCI), inhibits ciliary maintenance inChlamydomonasand hTERT-RPE1 cells and assembly inChlamydomonas. These effects involve inhibition of total protein synthesis, microtubule organization, membrane trafficking, and KAP-GFP motor dynamics. Our data provide evidence for various avenues for BCI-induced ciliary shortening and impaired ciliogenesis that gives mechanistic insight into how MAP kinases can regulate ciliary length.

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“…Considering that AURKA plays a key role in ciliary disassembly, and GBM cells constantly assemble and disassemble their cilia while proliferating, it was surprising to not observe increased GBM cilia frequency after Alisertib treatment. It is possible that AURKA inhibition in GBM cells stimulates activity of other molecules that promote ciliary disassembly such as HDAC6, NEK and others (for review see: (22, 35, 36)). However, we previously reported that overexpression of HDAC6 in our L0 or S7 glioma cells did not reduce cilia frequency or length (32).…”

Section: Discussionmentioning

confidence: 99%

Aurora Kinase A Inhibition plus Tumor Treating Fields Suppress Glioma Cell Proliferation in a Cilium-Independent Manner

Tian,

Mallinger,

Shi

et al. 2023

Preprint

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Tumor Treating Fields (TTFields) have been shown to extend the survival of glioblastoma (GBM) patients. TTFields interfere with a broad range of cellular processes which may contribute to their efficacy. Among these, TTFields disrupt primary cilia stability on GBM cells. Here we asked if concomitant treatment of TTFields with other agents that interfere with GBM ciliogenesis can further suppress GBM cell proliferation in vitro. Aurora Kinase A (AURKA) promotes both cilia disassembly and GBM growth in vitro and in xenograft models. Inhibitors of AURKA such as Alisertib have been previously demonstrated to inhibit cilia disassembly and increase the frequency of cilia in various cell types. However, here we show that physiological concentrations of Alisertib treatment significantly reduced GBM cilia frequency in gliomaspheres across multiple patient derived cell lines, and in patient biopsies treated ex vivo with Alisertib. This activity of Alisertib seems to be glioma cell specific as it did not reduce neuronal or glial cilia frequencies in mixed primary cell cultures from mouse forebrain. Furthermore, Alisertib depletion of glioma cilia appears specific to AURKA inhibition, as a potent AURKB inhibitor, AZD1152, had no effect on GBM ciliary frequency. Treatment of two different GBM patient-derived cell lines with TTFields and Alisertib resulted in a significant reduction in cell proliferation compared to either treatment alone. However, this effect was not cilia-dependent as the combined treatment reduced proliferation in cilia-depleted cell lines lacking,ARL13b, or U87MG cells which are naturally devoid of ARL13B+cilia. This result is not surprising given the wide range of pathways regulated by AURKA in addition to cilia. Nonetheless, Alisertib-mediated effects on glioma cilia may be a useful biomarker of drug efficacy within tumor tissue. Considering Alisertib has been shown to cross the blood brain barrier and inhibit intracranial growth of xenografted tumor models, our data warrant future studies to explore whether concomitant Alisertib and TTFields exposure prolongs survival of brain tumor-bearing animals in vivo.

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Insights into the Regulation of Ciliary Disassembly

Cited by 23 publications

References 119 publications

Bardet-Biedl Syndrome: Current Perspectives and Clinical Outlook

Bardet-Biedl Syndrome: Current Perspectives and Clinical Outlook

The ERK activator, BCI, inhibits ciliogenesis and causes defects in motor behavior, ciliary gating, and cytoskeletal rearrangement

Aurora Kinase A Inhibition plus Tumor Treating Fields Suppress Glioma Cell Proliferation in a Cilium-Independent Manner

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