XPO1-dependent nuclear export as a target for cancer therapy

Azizian, Nancy G.; Li, Yulin

doi:10.1186/s13045-020-00903-4

Cited by 149 publications

(177 citation statements)

References 105 publications

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“…XPO1 overexpression is commonly observed in solid cancers and haematological malignancies, leading to the aberrant localisations of tumour suppressors and cell cycle regulators, and to enhanced expressions of oncogenes associated with poor prognoses [ 7 , 39 ]. Interestingly, Ran, an XPO1/IPO1 partner, necessary for proper nucleocytoplasmic export and import, is also overexpressed and associated with a poor prognosis in solid cancers [ 49 , 50 ].…”

Section: Resultsmentioning

confidence: 99%

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XPO1E571K Mutation Modifies Exportin 1 Localisation and Interactome in B-Cell Lymphoma

Miloudi

Bohers

Guilhot

et al. 2020

Cancers

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The XPO1 gene encodes exportin 1 (XPO1) that controls the nuclear export of cargo proteins and RNAs. Almost 25% of primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma (cHL) cases harboured a recurrent XPO1 point mutation (NM_003400, chr2:g61718472C>T) resulting in the E571K substitution within the hydrophobic groove of the protein, the site of cargo binding. We investigated the impact of the XPO1E571K mutation using PMBL/cHL cells having various XPO1 statuses and CRISPR–Cas9-edited cells in which the E571K mutation was either introduced or knocked-out. We first confirmed that the mutation was present in both XPO1 mRNA and protein. We observed that the mutation did not modify the export capacity but rather the subcellular localisation of XPO1 itself. In particular, mutant XPO1 bound to importin β1 modified the nuclear export/import dynamics of relevant cargoes.

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Section: Resultsmentioning

confidence: 99%

“…There is a growing interest in targeting XPO1 in cancer treatment, and various SINEs have been developed, including Selinexor, and are still under development [ 7 , 39 ]. Selinexor exhibits a great therapeutic efficacy either alone or in combination therapies and is currently being assayed in numerous clinical trials ( ).…”

Section: Discussionmentioning

confidence: 99%

XPO1E571K Mutation Modifies Exportin 1 Localisation and Interactome in B-Cell Lymphoma

Miloudi

Bohers

Guilhot

et al. 2020

Cancers

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“…We also identified IGF-1R, a key tyrosine kinase receptor in regulating cancer cell survival, proliferation, and motility (24). In addition, a number of unreported genes were also listed, including XPO1 and IPO4 (cytoplasm-nucleus shuttle (25,26)), SLC25A5, SLC25A6 and SLC3A2 (ADP/ATP transportation from mitochondria to cytoplasm, as well as heteromeric amino acid and polyamine transportation (27,28)), and UBA1 and UBE3C (ubiquitin-proteasome degradation (29,30)). In this study, we established gene IRS4 as our top candidate for the following reasons: (1) It was #3 in mass spectrometry score ranking.…”

Section: Mass Spectrometry Analysis Identified Irs4 As a Novel Substrmentioning

confidence: 99%

FER-mediated tyrosine phosphorylation and PIK3R2/p85β recruitment on IRS4 promotes the PI3K-AKT signaling pathway and tumorigenesis in ovarian cancer

Zhang

Xiong

Zhu

et al. 2020

Preprint

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Tyrosine phosphorylation, orchestrated by tyrosine kinases and phosphatases, modulates a multi-layered signaling network in a time and space dependent manner. Dysregulation of this post-translational modification is inevitably associated with pathological diseases. Our previous work has demonstrated that non-receptor tyrosine kinase FER is upregulated in ovarian cancer. Knockdown of the kinase attenuates metastatic phenotypes in tumor cells. Here we employed mass spectrometry and biochemical approaches to identify IRS4 as a novel substrate of FER. Using a proximity-based tagging system, we determined that FER-mediated phosphorylation of Tyr779 enables IRS4 to recruit PIK3R2/p85β, the regulatory subunit of PI-3K, and activate the PI3K-AKT pathway. Rescuing IRS4-null ovarian tumor cells with phosphorylation-defective mutant, but not WT IRS4, delayed tumor cell proliferation both in vitro and in vivo. Overall, we revealed a kinase-substrate regulatory mode between FER and IRS4, and the pharmacological inhibition of FER kinase may be beneficial for ovarian cancer patients with PI3K-AKT hyperactivation.

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“…Selinexor is a first in class orally bioavailable inhibitor of Exportin-1 (XPO1) ( Syed, 2019 ). XPO1 is an export receptor for various proteins and RNA molecules with oncogenic properties and is frequently altered in cancer ( Azizian and Li, 2020 ). Moreover, it is implicated in several cancer pathways including cell growth and survival, differentiation, and drug resistance ( Nachmias and Schimmer, 2020 ).…”

Section: Potential Anticancer Drugs For Covid-19mentioning

confidence: 99%

Repurposing anticancer drugs for the management of COVID-19

Bairi

Trapani

Petrillo

et al. 2020

European Journal of Cancer

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Since its outbreak in the last December, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has rapidly spread worldwide at a pandemic proportion, thus regarded as a global public health emergency. The existing therapeutic options for COVID-19 beyond the intensive supportive care are limited, with an undefined or modest efficacy reported so far. Drug repurposing represents an enthusiastic mechanism to use approved drugs outside the scope of their original indication and accelerate the discovery of new therapeutic options. With the emergence of COVID-19, drug repurposing has been largely applied for early clinical testing. In this Review , we discuss some repurposed anticancer drugs for the treatment of COVID-19 and under investigation in clinical trials or proposed for the clinical testing. .

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XPO1-dependent nuclear export as a target for cancer therapy

Cited by 149 publications

References 105 publications

XPO1E571K Mutation Modifies Exportin 1 Localisation and Interactome in B-Cell Lymphoma

XPO1E571K Mutation Modifies Exportin 1 Localisation and Interactome in B-Cell Lymphoma

FER-mediated tyrosine phosphorylation and PIK3R2/p85β recruitment on IRS4 promotes the PI3K-AKT signaling pathway and tumorigenesis in ovarian cancer

Repurposing anticancer drugs for the management of COVID-19

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