Targeting nucleocytoplasmic transport in cancer therapy

Hill, Richard; Cautain, Bastien; Pedro, Nuria de; Link, Wolfgang

doi:10.18632/oncotarget.1457

Cited by 95 publications

(81 citation statements)

References 139 publications

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“…However, in several types of cancer (including colon cancer, breast cancer, ovarian cancer, retinoblastoma, and neuroblastoma), wild-type p53 is inactivated due to abnormal subcellular localization [51]. In these situations, the function and activity of p53 remains intact.…”

Section: Inactivation Of Tp53 By Mislocalizationmentioning

confidence: 99%

Loss of Tumor Suppressor Gene Function in Human Cancer: An Overview

Wei¹,

Wu²,

Rajasekaran³

et al. 2018

Cell Physiol Biochem

266

142

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Cancer is a disease caused by the accumulation of genetic and epigenetic changes in two types of genes: tumor suppressor genes (TSGs) and proto-oncogenes. Extensive research has been conducted over the last few decades to elucidate the role of TSGs in cancer development. In cancer, loss of TSG function occurs via the deletion or inactivation of two alleles, according to Knudson’s two-hit model hypothesis. It has become clear that mutations in TSGs are recessive at the level of an individual cell; therefore, a single mutation in a TSG is not sufficient to cause carcinogenesis. However, many studies have identified candidate TSGs that do not conform with this standard definition, including genes inactivated by epigenetic silencing rather than by deletion. In addition, proteasomal degradation by ubiquitination, abnormal cellular localization, and transcriptional regulation are also involved in the inactivation of TSGs. This review incorporates these novel additional mechanisms of TSG inactivation into the existing two-hit model and proposes a revised multiple-hit model that will enable the identification of novel TSGs that can be used as prognostic and predictive biomarkers of cancer.

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Section: Inactivation Of Tp53 By Mislocalizationmentioning

confidence: 99%

Loss of Tumor Suppressor Gene Function in Human Cancer: An Overview

Wei¹,

Wu²,

Rajasekaran³

et al. 2018

Cell Physiol Biochem

266

142

View full text Add to dashboard Cite

show abstract

“…For example, aberrant cytoplasmic localization of a physiologically nuclear tumor suppressor protein may render this protein inactive, and thus contribute to tumorigenesis. In fact, mislocalization of cancer-related proteins, including the products of prominent oncogenes and tumor suppressor genes, has been often demonstrated in human tumors [63,[64][65][66] .…”

Section: Altered Nucleocytoplasmic Localization Of Proteins In Cancermentioning

confidence: 99%

Hitting a moving target: inhibition of the nuclear export receptor XPO1/CRM1 as a therapeutic approach in cancer

Sendino¹,

Omaetxebarria²,

Rodríguez³

2018

CDR

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Cellular homeostasis crucially relies on the correct nucleocytoplasmic distribution of a vast number of proteins and RNA molecules, which are shuttled in and out of the nucleus by specialized transport receptors. The nuclear export receptor XPO1, also called CRM1, mediates the translocation of hundreds of proteins and several classes of RNA to the cytoplasm, and thus regulates critical signaling pathways and cellular functions. The normal function of XPO1 appears to be often disrupted in malignant cells due to gene mutations or, most commonly, aberrant overexpression. Due to its important physiological roles and its frequent alteration in human tumors, XPO1 is a promising target for cancer therapy. XPO1 inhibitors have undergone extensive testing as therapeutic agents in preclinical models of cancer, with promising results. One of these inhibitors, Selinexor, is currently being evaluated in multiple clinical trials of different types of solid tumors and hematological malignancies. Here, we review several key aspects of XPO1 function, as well as the mechanisms that may lead to its alteration in cancer, and provide an update on the status of XPO1 inhibitors being developed as drugs for cancer therapy, including the definitive results of the first clinical trials with Selinexor that have been recently published. Figure 1. Receptor-mediated nucleocytoplasmic transport of proteins. A: Illustrative overview of the nuclear import of a cargo protein bearing a "classical" NLS mediated by the Importina/Importinb heterodimer (left) and the nuclear export of a cargo protein bearing a "leucine-rich" NES mediated by XPO1 (right); B: schematic depiction of the nuclear pore complex, illustrating its main structural features; C: examples of nucleocytoplasmic transport signals. The NLSs of SV40 large T antigen (monopartite) and nucleoplasmin (bipartite) are shown, with the basic residues that characterize "classical" NLSs highlighted in red. Below, the NES of PKI and a general consensus sequence of "leucine-rich" NESs are shown. The characteristic hydrophobic residues (represented by f in the consensus) are highlighted in colors and underlined. NLS: nuclear localization signal; NES: nuclear export signal Conception of the work, draft and revision of the work: Sendino M, Omaetxebarria MJ, Rodríguez JA

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“…13 The most common (canonical) mechanism 14 involves a heterodimer, importin α/β, which binds to NLS-bearing cargoes resulting in translocation of the importin/cargo complex through the NPC. 15 Although, some proteins and viruses have been found to translocate from the cytoplasm to the nucleus facilitated by importin β without the aid of importin α, 16,17 this non-canonical mechanism of nucleocytoplasmic transport is relatively underexplored. Importin β is overexpressed in cervical, ovarian, and esophageal cancers, 18 among others, and its function is also involved in the internalization of viruses, 17 making it a potential therapeutic target in cancers and viral infections.…”

mentioning

confidence: 99%

A Carbon Nanotube Optical Sensor Reports Nuclear Entry via a Noncanonical Pathway

et al. 2017

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Single-walled carbon nanotubes are of interest in biomedicine for imaging and molecular sensing applications, and as shuttles for various cargos such as chemotherapeutic drugs, peptides, proteins, and oligonucleotides. Carbon nanotube surface chemistry can be modulated for subcellular targeting while preserving photoluminescence for label-free visualization in complex biological environments, making them attractive materials for such studies. The cell nucleus is a potential target for many pathologies including cancer and infectious diseases. Understanding mechanisms of nanomaterial delivery to the nucleus may facilitate diagnostics, drug development, and gene editing tools. Currently, there are no systematic studies to understand how these nanomaterials gain access to the nucleus. Herein, we developed carbon nanotube-based hybrid material which elucidated a distinct mechanism of nuclear translocation of a nanomaterial in cultured cells. We developed a nuclear-targeted nanotube via cloaking photoluminescent single-walled carbon nanotubes in a guanidinium-functionalized helical polycarbodiimide. We found that the nuclear entry of the nanotubes was mediated by the import receptor importin β without the aid of importin α and not by the more common importin α/β pathway. Additionally, the nanotube photoluminescence exhibited distinct red-shifting upon entry to the nucleus, potentially functioning as a reporter of the importin β-mediated nuclear transport process. This work delineates a non-canonical mechanism for nanomaterial delivery to the nucleus and provides a reporter for the study of nucleus-related pathologies.

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Targeting nucleocytoplasmic transport in cancer therapy

Cited by 95 publications

References 139 publications

Loss of Tumor Suppressor Gene Function in Human Cancer: An Overview

Loss of Tumor Suppressor Gene Function in Human Cancer: An Overview

Hitting a moving target: inhibition of the nuclear export receptor XPO1/CRM1 as a therapeutic approach in cancer

A Carbon Nanotube Optical Sensor Reports Nuclear Entry via a Noncanonical Pathway

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