The Tumor Suppressor pVHL Down-regulates Never-in-Mitosis A-related Kinase 8 via Hypoxia-inducible Factors to Maintain Cilia in Human Renal Cancer Cells

Ding, Xiaofei; Zhou, Jun; Hu, Quan; Liu, Shuangchun; Chen, Guang

doi:10.1074/jbc.m114.589226

Cited by 33 publications

(34 citation statements)

References 31 publications

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“…In addition, ganetespib and the proteasomal inhibitors each significantly induced NEK8 (Fig. 2), another protein linked to ciliary disassembly, although not yet directly connected to AURKA (40, 41), but this did not affect expression of PP2A (Fig. 2), a phosphatase that negatively regulates AURKA activation (36).…”

Section: Resultsmentioning

confidence: 99%

Ganetespib limits ciliation and cystogenesis in autosomal‐dominant polycystic kidney disease (ADPKD)

et al. 2018

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Autosomal-dominant polycystic kidney disease (ADPKD) is associated with progressive formation of renal cysts, kidney enlargement, hypertension, and typically end-stage renal disease. In ADPKD, inherited mutations disrupt function of the polycystins (encoded by PKD1 and PKD2), thus causing loss of a cyst-repressive signal emanating from the renal cilium. Genetic studies have suggested ciliary maintenance is essential for ADPKD pathogenesis. Heat shock protein 90 (HSP90) clients include multiple proteins linked to ciliary maintenance. We determined that ganetespib, a clinical HSP90 inhibitor, inhibited proteasomal repression of NEK8 and the Aurora-A activator trichoplein, rapidly activating Aurora-A kinase and causing ciliary loss in vitro. Using conditional mouse models for ADPKD, we performed long-term (10 or 50 wk) dosing experiments that demonstrated HSP90 inhibition caused durable in vivo loss of cilia, controlled cystic growth, and ameliorated symptoms induced by loss of Pkd1 or Pkd2. Ganetespib efficacy was not increased by combination with 2-deoxy-d-glucose, a glycolysis inhibitor showing some promise for ADPKD. These studies identify a new biologic activity for HSP90 and support a cilia-based mechanism for cyst repression.-Nikonova, A. S., Deneka, A. Y., Kiseleva, A. A., Korobeynikov, V., Gaponova, A., Serebriiskii, I. G., Kopp, M. C., Hensley, H. H., Seeger-Nukpezah, T. N., Somlo, S., Proia, D. A., Golemis, E. A. Ganetespib limits ciliation and cystogenesis in autosomal-dominant polycystic kidney disease (ADPKD).

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Section: Resultsmentioning

confidence: 99%

Ganetespib limits ciliation and cystogenesis in autosomal‐dominant polycystic kidney disease (ADPKD)

et al. 2018

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“…Reduced ciliary expression has been also reported in renal cell carcinomas [25, 31–33]. In the most characterized tumor ( i.e.…”

Section: Primary Cilia Fate In Cancermentioning

confidence: 98%

Primary Cilia in Tumor Biology: The Primary Cilium as a Therapeutic Target in Cholangiocarcinoma

Gradilone

Pisarello

LaRusso

2017

CDT

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Cilia are microtubule-based organelles, which are ubiquitously expressed in epithelial cells. Cholangiocytes, the epithelial cells lining the biliary tree, have primary cilia extending from their apical plasma membrane into the ductal lumen, where the cilia function as multisensory organelles transducing environmental cues into the cell interior. The decrease or loss of primary cilia has been described in several malignancies, including cholangiocarcinoma, suggesting that the loss of cilia is a common occurrence in neoplastic transformation. In this short review, we describe the expression of cilia in several cancers, explore the mechanisms and consequences of ciliary loss, and discuss the potential use of the primary cilia as therapeutic targets.

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“…1). The 786-O RCC line is defective in VHL expression, as it harbors mutated VHL [53, 54] with altered HIF and VEGF (Vascular endothelial growth factor) pathways [46] and gives rise to clear cell tumors in nude mice [55, 56]. In this RCC model the vast majority (122/160) of genes induced by hypoxia in wt-VHL transfected 786-O ( VHL + ) cells are not significantly up-regulated in VHL mutated 786-O cells, confirming that the loss of VHL is not equivalent to hypoxic exposure and that in RCC, the VHL tumor suppressor has a distinct role from its activity in the hypoxia-inducible pathway [57].…”

Section: Introductionmentioning

confidence: 99%

Choosing the right cell line for renal cell cancer research

Brodaczewska¹,

Szczylik²,

et al. 2016

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Cell lines are still a tool of choice for many fields of biomedical research, including oncology. Although cancer is a very complex disease, many discoveries have been made using monocultures of established cell lines. Therefore, the proper use of in vitro models is crucial to enhance our understanding of cancer. Therapeutics against renal cell cancer (RCC) are also screened with the use of cell lines. Multiple RCC in vitro cultures are available, allowing in vivo heterogeneity in the laboratory, but at the same time, these can be a source of errors. In this review, we tried to sum up the data on the RCC cell lines used currently. An increasing amount of data on RCC shed new light on the molecular background of the disease; however, it revealed how much still needs to be done. As new types of RCC are being distinguished, novel cell lines and the re-exploration of old ones seems to be indispensable to create effective in vitro tools for drug screening and more.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-016-0565-8) contains supplementary material, which is available to authorized users.

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The Tumor Suppressor pVHL Down-regulates Never-in-Mitosis A-related Kinase 8 via Hypoxia-inducible Factors to Maintain Cilia in Human Renal Cancer Cells

Cited by 33 publications

References 31 publications

Ganetespib limits ciliation and cystogenesis in autosomal‐dominant polycystic kidney disease (ADPKD)

Ganetespib limits ciliation and cystogenesis in autosomal‐dominant polycystic kidney disease (ADPKD)

Primary Cilia in Tumor Biology: The Primary Cilium as a Therapeutic Target in Cholangiocarcinoma

Choosing the right cell line for renal cell cancer research

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