Controlling the Gatekeeper: Therapeutic Targeting of Nuclear Transport

Kosyna, Friederike Katharina; Depping, Reinhard

doi:10.3390/cells7110221

Cited by 67 publications

(76 citation statements)

References 141 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We found that KPNA4 silencing caused reduction of nuclear GFP NLS amounts while cytoplasmic GFP NLS levels was increased upon KPNA4 knockdown (Fig. 2b, c), suggesting KPNA4 mediates NLS-dependent nuclear imports [24].…”

Section: Kpna4 Is Required For Cellular Malignancy and Regulates Globmentioning

confidence: 79%

“…2a). First, we investigated NLS-dependent nuclear transport in those cells since NLSdependent nuclear import is dominantly regulated by Karyopheryin family [24]. To investigate the role of KPNA4 on nuclear import ability, GFP harboring SV40-derived NLS (GFP NLS ) was generated ( Supplementary Fig.…”

Section: Kpna4 Is Required For Cellular Malignancy and Regulates Globmentioning

confidence: 99%

See 1 more Smart Citation

Disease-specific alteration of karyopherin-α subtype establishes feed-forward oncogenic signaling in head and neck squamous cell carcinoma

et al. 2019

View full text Add to dashboard Cite

Nuclear import, mediated in part by karyopherin-α (KPNA)/importin-α subtypes, regulates transcription factor access to the genome and determines cell fate. However, the cancer-specific changes of KPNA subtypes and the relevancy in cancer biology remain largely unknown. Here, we report that KPNA4, encoding karyopherin-α4 (KPNA4), is exclusively amplified and overexpressed in head and neck of squamous cell carcinoma (HNSCC). Depletion of KPNA4 attenuated nuclear localization signal-dependent transport activity and suppressed malignant phenotypes and induced epidermal differentiation. Mechanistically, KPNA4-mediated nuclear transport of Ras-responsive element-binding protein (RREB1), which sustains Ras/ERK pathway signaling through repressing miR-143/145 expression. Notably, MAPK signaling enhanced trafficking activity of KPNA4 via phosphorylation of KPNA4 at Ser60. These data reveal that KPNA4 establishes a feed-forward cascade that potentiates Ras/ERK signaling in HNSCC.

show abstract

Section: Kpna4 Is Required For Cellular Malignancy and Regulates Globmentioning

confidence: 79%

Section: Kpna4 Is Required For Cellular Malignancy and Regulates Globmentioning

confidence: 99%

Disease-specific alteration of karyopherin-α subtype establishes feed-forward oncogenic signaling in head and neck squamous cell carcinoma

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Since the discovery of LMB, an increasing number of new inhibitors of nuclear transport mediated by importins have been reported, but all retain their persistent toxicity due to their lack of specificity. On the contrary, a limited number of inhibitors that target specific cargos have been reported (25,26). The first cargo-specific nuclear transport inhibitor described was mifepristone, a specific inhibitor of recognition of HIV-1 integrase by importin-α/β (27).…”

Section: Discussionmentioning

confidence: 99%

ZZW-115–dependent inhibition of NUPR1 nuclear translocation sensitizes cancer cells to genotoxic agents

Lan¹,

Santofimia‐Castaño²,

Swayden³

et al. 2020

JCI Insight

View full text Add to dashboard Cite

“…Progress in the development of drugs altering transport processes has been made. 40 Accordingly, in July 2019, the first and only nuclear export inhibitor has been approved by the FDA. The accelerated FDA approval of Selinexor (XPOVIO TM ) is based on a 25.3% response rate seen in the Phase 2b Selinexor Treatment of Refractory Myeloma (STORM) trial (NCT02336815).…”

Section: Discussionmentioning

confidence: 99%

<p>The Nuclear Export Inhibitor Selinexor Inhibits Hypoxia Signaling Pathways And 3D Spheroid Growth Of Cancer Cells</p>

Depping

Fallois

Landesman

et al. 2019

OTT

Self Cite

View full text Add to dashboard Cite

Purpose: The nucleocytoplasmic transport of macromolecules is critical for both cell physiology and pathophysiology. Exportin 1 (XPO1), the major nuclear export receptor, is involved in the cellular adaptation to reduced oxygen availability by controlling the nuclear activity of the hypoxia-inducible factors (HIFs). Recently, a specific inhibitor of XPO1, selinexor (KPT-330), has been identified that inhibits nuclear export of cargo proteins by binding to the XPO1 cargo-binding pocket. Patients and methods: We used different cancer cell lines from human tissues and evaluated the physiological activity of selinexor on the hypoxia response pathway in twodimensional (2D) monolayer cell cultures in quantitative real-time (qRT)-PCR experiments and luciferase reporter gene assays. A three-dimensional (3D) tumor spheroid culture model of MCF-7 breast cancer cells was established to analyze the effect of selinexor on 3D tumor spheroid structure, formation and viability. Results: Selinexor treatment reduces HIF-transcriptional activity and expression of the HIF-1 target gene solute carrier family 2 member 1 (SLC2A1). Moreover, 3D tumor spheroid structure, formation and viability are inhibited in response to selinexor-induced nuclear export inhibition. Conclusion: Here, we demonstrate the effect of specific XPO1-inhibition on the hypoxic response on the molecular level in 2D and 3D culture models of MCF-7 cells.

show abstract

Controlling the Gatekeeper: Therapeutic Targeting of Nuclear Transport

Cited by 67 publications

References 141 publications

Disease-specific alteration of karyopherin-α subtype establishes feed-forward oncogenic signaling in head and neck squamous cell carcinoma

Disease-specific alteration of karyopherin-α subtype establishes feed-forward oncogenic signaling in head and neck squamous cell carcinoma

ZZW-115–dependent inhibition of NUPR1 nuclear translocation sensitizes cancer cells to genotoxic agents

<p>The Nuclear Export Inhibitor Selinexor Inhibits Hypoxia Signaling Pathways And 3D Spheroid Growth Of Cancer Cells</p>

Contact Info

Product

Resources

About