Poor prognosis of nucleophosmin overexpression in solid tumors: a meta-analysis

Chen, Siying; He, Hairong; Wang, Yan; Liu, Leichao; Liu, Yang; You, Haisheng; Dong, Yalin; Lyu, Jun

doi:10.1186/s12885-018-4718-6

Cited by 15 publications

(12 citation statements)

References 35 publications

(48 reference statements)

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“…In the proteomic study by Cruz et al [28], PEO1CarbR cells expressed more NPM1 than the parental PEO1 line, in line with the relative sensitivity to CX-5461, pointing to a protective role of the protein to the effects of this drug. Olausson et al [31] silenced NMP1 in human glioma cells which, when treated with the RNA polymerase I inhibitor Actinomycin D, sensitized cells to drug-induced apoptosis, in some agreement with our findings. This warrants further investigation of the sensitivity of cell lines with varying levels of NPM1 to the effects of CX-5461+/− radiation but this is beyond the scope of the current paper.…”

Section: Discussionsupporting

confidence: 92%

“…It has been shown that NPM1 is overexpressed in drug-resistant ovarian cancer cells using an in-depth proteomic mass spectrometry study [28,29]. In addition, in high-grade ovarian serous cancer [30], a poorer patient outcome was associated with a significant overexpression of nuclear NPM1 and in transformed ovarian cancer cells [31], elevated levels of NPM1 were reported. Silencing of NPM1 expression by Kalra et al [31] led to aberrant double-strand break repair and p53/p21-mediated apoptosis.…”

Section: Discussionmentioning

confidence: 99%

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The Targeting of RNA Polymerase I Transcription Using CX-5461 in Combination with Radiation Enhances Tumour Cell Killing Effects in Human Solid Cancers

Ismael

Webb

Ajaz

et al. 2019

Cancers

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An increased rate of cellular proliferation is a hallmark of cancer and may be accompanied by an increase in ribosome biogenesis and dysregulation in rRNA synthesis. In this regard, CX-5461 has been developed as a novel RNA polymerase I inhibitor and is currently in Phase I/II clinical trials for solid and hematological malignancies. In the present study, interactions between CX-5461 and single-dose X-ray exposure were assessed using isobologram analysis using MTS assay and drug-induced cell death was assessed using flow cytometric, confocal microscopy and Western blot analysis. Combination treatments involving CX-5461 and single-dose X-ray exposure highlighted increased effectiveness compared to individual treatment alone in the CaSki cervical cancer line, with marked synergistic interaction occurring within the low-drug (50 nM) and low-dose radiation range (2–6 Gy). Cell lines challenged with CX-5461 demonstrated the presence of DNA damage, induction of apoptosis, autophagy and senescence alongside high percentages of G2/M cell cycle arrest. In addition, we report preferential sensitivity of ovarian cancer cells with BRCA2 mutation to this novel agent. Taken together, CX-5461 displayed a broad spectrum of activity in a panel of solid cancer cell lines with IC50 values ranging from 35 nM to >1 µM. The work described herein identifies the synergistic effects of CX-5461 in combination with X-rays in solid cancers and may also aid in the design of clinical trials involving this novel agent.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

The Targeting of RNA Polymerase I Transcription Using CX-5461 in Combination with Radiation Enhances Tumour Cell Killing Effects in Human Solid Cancers

Ismael

Webb

Ajaz

et al. 2019

Cancers

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“…Notably, NPM1 is overexpressed in a wide spectrum of solid human cancers including prostate [43], ovaries [44], nonsmall cell lung [45], liver [46], thyroid [47], colon [48], pancreas [49], as well as glioma [50], glioblastoma [51] and astrocytoma [52]. It has been highlighted that, in some cases, NPM1 increased expression correlates with the mitotic index and with the stage of tumor progression [1,53]. Even if the role of NPM1 overexpression in cancerogenesis is far to be fully understood, various scenarios have been proposed including the association of its overexpression with the upregulation of ribosome biogenesis and protein synthesis [54], but also with the stimulation of DNA repair following oncogene activation and with reduced apoptotic response [15,55].…”

Section: Role In Cancermentioning

confidence: 99%

Nucleophosmin in Its Interaction with Ligands

Cela

Matteo

Federici

2020

IJMS

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Nucleophosmin (NPM1) is a mainly nucleolar protein that shuttles between nucleoli, nucleoplasm and cytoplasm to fulfill its many functions. It is a chaperone of both nucleic acids and proteins and plays a role in cell cycle control, centrosome duplication, ribosome maturation and export, as well as the cellular response to a variety of stress stimuli. NPM1 is a hub protein in nucleoli where it contributes to nucleolar organization through heterotypic and homotypic interactions. Furthermore, several alterations, including overexpression, chromosomal translocations and mutations are present in solid and hematological cancers. Recently, novel germline mutations that cause dyskeratosis congenita have also been described. This review focuses on NPM1 interactions and inhibition. Indeed, the list of NPM1 binding partners is ever-growing and, in recent years, many studies contributed to clarifying the structural basis for NPM1 recognition of both nucleic acids and several proteins. Intriguingly, a number of natural and synthetic ligands that interfere with NPM1 interactions have also been reported. The possible role of NPM1 inhibitors in the treatment of multiple cancers and other pathologies is emerging as a new therapeutic strategy.

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“…This is in agreement with nucleolar activity being broadly upregulated in cancers ( Montanaro et al, 2008 ). Furthermore, other ribosome biogenesis factors, such as the Pol I transcription machinery and nucleophosmin, are also upregulated in cancer ( Bywater et al, 2013 ; Chen et al, 2018 ). We found concomitant upregulation of Treacle and UBF, nucleolin, and Pol I in lung and stomach cancer whereas a variable degree of overlap was observed in other cancer types.…”

Section: Discussionmentioning

confidence: 99%

Treacle is Upregulated in Cancer and Correlates With Poor Prognosis

Oxe

Larsen

2022

Front. Cell Dev. Biol.

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Treacle/TCOF1 is an adaptor protein specifically associated with nucleolar chromatin. In the nucleolus it stimulates ribosome biogenesis, thereby promoting growth and proliferation. A second role of Treacle has emerged as a coordinator of the nucleolar responses to DNA damage, where it facilitates nucleolar DNA repair and cellular survival after genotoxic insults. The involvement of Treacle in multiple fundamental processes such as growth, proliferation, and genome stability, which are tightly linked to cancer, raises the question of Treacle’s role in the development of this disease. On one hand, overexpression of Treacle could stimulate nucleolar transcription and ribosome biogenesis providing a growth advantage in cancer cells. On the other hand, the function of Treacle as a gatekeeper in response to nucleolar DNA damage could favor mutations that would impair its function. In this perspective, we analyze paired Treacle expression data from the Cancer Genome Atlas (TCGA) and correlate expression with patient survival in different cancer types. We also discuss other recently published observations of relevance to the role of Treacle in cancer. In light of these new observations, we propose possible roles of Treacle in carcinogenesis and discuss its potential as a therapeutic target.

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Poor prognosis of nucleophosmin overexpression in solid tumors: a meta-analysis

Cited by 15 publications

References 35 publications

The Targeting of RNA Polymerase I Transcription Using CX-5461 in Combination with Radiation Enhances Tumour Cell Killing Effects in Human Solid Cancers

The Targeting of RNA Polymerase I Transcription Using CX-5461 in Combination with Radiation Enhances Tumour Cell Killing Effects in Human Solid Cancers

Nucleophosmin in Its Interaction with Ligands

Treacle is Upregulated in Cancer and Correlates With Poor Prognosis

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