AS1411-Induced Growth Inhibition of Glioma Cells by Up-Regulation of p53 and Down-Regulation of Bcl-2 and Akt1 via Nucleolin

Cheng, Ye; Zhao, Gang; Zhang, Siwen; Nigim, Fares; Zhou, Guangtong; Yu, Zhiyun; Song, Yang; Chen, Yong; Li, Yunqian

doi:10.1371/journal.pone.0167094

Cited by 55 publications

(52 citation statements)

References 51 publications

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“…It has also been associated with poor prognosis for a variety of types of cancer (24,25). For example, nucleolin inhibits P53 and enhances Bcl-2 and protein kinase B (Akt) expression to promote the proliferation of human glioma cells (26). Other studies demonstrated that phosphorylation of nucleolin may be associated with cancer metastasis and cell proliferation (16,18).…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of nucleolin is indispensable to its involvement in the proliferation and migration of non-small cell lung cancer cells

Huang

Tan

et al. 2018

Oncol Rep

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Non-small cell lung cancer (NSCLC) is one of the mostly deadly malignancies in the world. Nucleolin is a multifunctional protein that mainly regulates ribosome biogenesis but also has other functions including modulating the transcription of mRNAs and repressing RNA polymerase II. Nucleolin is overexpressed in various cancer cells, including NSCLC cells. It can confer resistance to apoptosis and promote cell migration and blood vessel formation by directly taking part in various tumor signal transduction pathways. The activities of nucleolin are regulated mainly by intracellular localization and post-translational modifications, including phosphorylation, glycosylation, methylation, and ADP-ribosylation. Phosphorylation of nucleolin (P-nucleolin) in NSCLC cells is still not well characterized. In the present study, the levels of nucleolin and P-nucleolin were examined in lung tissue and cells and it was demonstrated that levels of the two forms of nucleolin were significantly increased in NSCLC compared with non-cancerous tissues and cells. In addition, it was demonstrated that high expression levels of nucleolin and P-nucleolin were significantly associated with poor overall survival of NSCLC patients. Doxorubicin (DOX) is a type of anthracycline that has been used in the treatment of various types of cancer, including NSCLC. Upregulation of nucleolin through exogenous expression of nucleolin promoted A549 cell proliferation and migration, while downregulation of nucleolin through expression of small interfering RNA-nucleolin attenuated A549 cell proliferation and migration. Following stimulation with DOX, A549 cell proliferation and migration decreased and the expression of P-nucleolin also decreased. In order to investigate whether P-nucleolin is indispensable to the proliferation and migration of NSCLC cells, a plasmid encoding mutant nucleolin, in which the phosphorylation site at threonine-76 was mutated to alanine, was constructed. Compared with the A549 cells transfected with wild-type nucleolin, P-nucleolin expression and cell proliferation and migration were significantly decreased in A549 cells transfected with mutant nucleolin. These results indicate that targeting P-nucleolin may be a promising strategy for treating NSCLC patients.

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Section: Discussionmentioning

confidence: 99%

Phosphorylation of nucleolin is indispensable to its involvement in the proliferation and migration of non-small cell lung cancer cells

Huang

Tan

et al. 2018

Oncol Rep

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“…We further observed that the TDP-43-dependent activation of apoptotic cell death in human cells was signi cantly reduced by NCL co-expression ( Fig. 9), suggesting that NCL could suppress TDP-43 toxicity also by directly acting as an antiapoptotic factor, in light of its reported ability to stabilize the mRNA of the Bcl-2 anti-apoptotic factor [95][96][97], and to modulate p53 signalling at multiple levels [98][99][100]. We indeed observed that NCL overexpression was able to rescue the normal Bcl-2 levels in TDP-43 overexpressing HEK293T cells, without, however, affecting Bcl-2 expression in cells expressing endogenous TDP-43 amounts.…”

Section: Discussionmentioning

confidence: 75%

Nucleolin rescues TDP-43 toxicity in yeast and human cell models

Peggion

Massimino

Stella

et al. 2020

Preprint

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Background TDP-43 is a nuclear protein involved in pivotal processes, extensively studied for its implication in neurodegenerative disorders. TDP-43 cytosolic inclusions are a common neuropathologic hallmark in amyotrophic lateral sclerosis (ALS) and related diseases, and it is now established that TDP-43 misfolding and aggregation play a key role in their etiopathology. TDP-43 neurotoxic mechanisms are not yet clarified, but the identification of proteins able to modulate TDP-43-mediated damage may provide crucial information to unveil the molecular basis of TDP-43 proteinopathies. Methods Here we generated and characterized novel models of TDP-43 toxicity in the yeast S. cerevisiae, which were used to investigate the effect of the nucleolar protein nucleolin (NCL) on TDP-43-damaged yeast cells, by employing multiple approaches (genetics, biochemistry, microscopy). We further characterized the NCL-TDP-43 relationship in human HEK293T cells, by the combination of biochemical and microscopy-based assays. Results We show for the first time that NCL acts as a potent suppressor of TDP-43 toxicity in yeast models, since NCL overexpression is able to rescue TDP-43-dependent damage on cell viability and morphology, by reducing the levels of TDP-43 aggregates, thus proteostatic stress. Interestingly, data in yeast cells point to the implication of the extra-nuclear fraction of NCL in the suppressive effect. We further provide evidence that NCL co-expression alleviates the TDP-43-induced toxicity also in HEK293T cells, as indicated by the restoration of cell viability, and the diminished apoptosis activation. Importantly, biochemical and microscopy data indicate that NCL protein in human cells reduces the amount of TDP-43 inclusions. Collectively, results in HEK293T cells further support the beneficial effects of NCL on TDP-43-dependent toxicity in a more consistent pathophysiological context. Conclusions Altogether, data in yeast and human cell models demonstrate that NCL potently supresses the cytotoxicity caused by the TDP-43 protein, and further suggest that NCL could act by promoting the TDP-43 nuclear retention, and thus reducing the formation of cytosolic TDP-43 toxic aggregates. Pinpointing NCL as a novel player in mediating TDP-43 toxicity, experimental evidence could support NCL as promising therapeutic target in ALS and ALS-related disorders.

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“…They have been investigated for a wide range of applications including imaging [133] and cancer therapeutics [131]. For example, AS1411, a Nucleolin specific aptamer, was the first oligodeoxynucleotide to reach phase I and II clinical trials for the treatment of cancers [134], including acute myeloid leukemia (NCT01034410) and renal cell carcinoma (NCT00740441). Additionally, Ye Cheng et al demonstrated in vitro and in vivo , the therapeutic potential of this aptamer for GBM.…”

Section: Assessing Rnai Delivery For Gbm Treatmentmentioning

confidence: 99%

“…Additionally, Ye Cheng et al demonstrated in vitro and in vivo , the therapeutic potential of this aptamer for GBM. Their results showed that treating U87-MG, U251, and SHG44 GBM cells with AS1411 reduced cell migration [134]. Local administration of AS1411 led to decreased tumor growth and prolonged overall survival in a subcutaneous U87-MG xenograft mouse model [134].…”

Section: Assessing Rnai Delivery For Gbm Treatmentmentioning

confidence: 99%

“…Their results showed that treating U87-MG, U251, and SHG44 GBM cells with AS1411 reduced cell migration [134]. Local administration of AS1411 led to decreased tumor growth and prolonged overall survival in a subcutaneous U87-MG xenograft mouse model [134]. Bioconjugation of aptamers to siRNA, miRNAs mimics, and anti-miR molecules have shown promising results in GBM cell lines [135,136].…”

Section: Assessing Rnai Delivery For Gbm Treatmentmentioning

confidence: 99%

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RNA interference for glioblastoma therapy: Innovation ladder from the bench to clinical trials

2017

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Glioblastoma multiforme (GBM) is the most common and deadliest type of primary brain tumor with a prognosis of 14 months after diagnosis. Current treatment for GBM patients includes “total” tumor resection, temozolomide-based chemotherapy, radiotherapy or a combination of these options. Although, several targeted therapies, gene therapy, and immunotherapy are currently in the clinic and/or in clinical trials, the overall survival of GBM patients has hardly improved over the last two decades. Therefore, novel multitarget modalities are urgently needed. Recently, RNA interference (RNAi) has emerged as a novel strategy for the treatment of most cancers, including GBM. RNAi-based therapies consist of using small RNA oligonucleotides to regulate protein expression at the post-transcriptional level. Despite the therapeutic potential of RNAi molecules, systemic limitations including short circulatory stability and low release into the tumor tissue have halted their progress to the clinic. The effective delivery of RNAi molecules through the blood-brain barrier (BBB) represents an additional challenge. This review focuses on connecting the translational process of RNAi-based therapies from in vitro evidence to pre-clinical studies. We delineate the effect of RNAi in GBM cell lines, describe their effectiveness in glioma mouse models, and compare the proposed drug carriers for the effective transport of RNAi molecules through the BBB to reach the tumor in the brain. Furthermore, we summarize the most important obstacles to overcome before RNAi-based therapy becomes a reality for GBM treatment.

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AS1411-Induced Growth Inhibition of Glioma Cells by Up-Regulation of p53 and Down-Regulation of Bcl-2 and Akt1 via Nucleolin

Cited by 55 publications

References 51 publications

Phosphorylation of nucleolin is indispensable to its involvement in the proliferation and migration of non-small cell lung cancer cells

Phosphorylation of nucleolin is indispensable to its involvement in the proliferation and migration of non-small cell lung cancer cells

Nucleolin rescues TDP-43 toxicity in yeast and human cell models

RNA interference for glioblastoma therapy: Innovation ladder from the bench to clinical trials

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