Interfering with the interaction between ErbB1, nucleolin and Ras as a potential treatment for glioblastoma

Goldshmit, Yona; Trangle, Sari Schokoroy; Kloog, Yoel; Pinkas‐Kramarski, Ronit

doi:10.18632/oncotarget.2343

Cited by 33 publications

(42 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In accord with previous reports (Farin et al., 2009), we can detect an association between EGFR and nucleolin, and this is increased in the presence of AS1411 (Supplementary Figure S10), consistent with the increased activation of EGFR under these conditions. These data are in contrast with a recent report that AS1411 inhibits the association of EGFR with nucleolin and decreases EGFR‐mediated signaling (Goldshmit et al., 2014). The inconsistencies between this recent paper and our current findings may be due to the use of different cell lines or conditions, or may add further weight to our suggestion that the activation of EGFR observed in our case may be a coincidental or secondary effect.…”

Section: Discussioncontrasting

confidence: 99%

Mechanistic studies of anticancer aptamer AS1411 reveal a novel role for nucleolin in regulating Rac1 activation

et al. 2015

View full text Add to dashboard Cite

AS1411 is a G-rich quadruplex-forming oligodeoxynucleotide that binds specifically to nucleolin, a protein found on the surface and in the cytoplasm of most malignant cells but absent from the surface/cytoplasm of most normal cells. AS1411 has shown promising clinical activity and is being widely used as a tumor-targeting agent, but its mechanism of action is not fully understood. Previously, we showed that AS1411 is taken up in cancer cells by macropinocytosis (fluid phase endocytosis) and subsequently stimulates further macropinocytosis by a nucleolin-dependent mechanism. In the current study, we have investigated the significance and molecular mechanisms of AS1411-induced macropinocytosis. Our results indicate that the antiproliferative activity of AS1411 in various cell lines correlated with its capacity to stimulate macropinocytosis. In DU145 prostate cancer cells, AS1411 induced activation of EGFR, Akt, p38, and Rac1. Activation of Akt and p38 were not critical for AS1411 activity because Akt activation was not observed in all AS1411-responsive cell lines and knockdown of p38 had no effect on AS1411's ability to inhibit proliferation. On the other hand, activation of EGFR and Rac1 appeared to play a role in AS1411 activity in all cancer cell lines examined (DU145, MDA-MB-468, A549, LNCaP) and their inhibition significantly reduced As1411-mediated macropinocytosis and AS1411 antiproliferative activity. Interestingly, downregulation of nucleolin expression by siRNA also produced a substantial increase in activated Rac1, revealing a previously unknown role for nucleolin as a negative regulator of Rac1 activation. Our results are consistent with a model whereby AS1411 binding to nucleolin leads to sustained activation of Rac1 and causes methuosis, a novel type of nonapoptotic cell death characterized by hyperstimulation of macropinocytosis. We speculate that methuosis is a tumor/metastasis suppressor mechanism that opposes the malignant functions of Rac1 and that cancer cells may overexpress nucleolin to surmount this barrier.

show abstract

Section: Discussioncontrasting

confidence: 99%

Mechanistic studies of anticancer aptamer AS1411 reveal a novel role for nucleolin in regulating Rac1 activation

et al. 2015

View full text Add to dashboard Cite

show abstract

“…AS1411 can be conjugated with blood-brain barrier (BBB) penetrating peptides which make it a good therapeutic agent for brain tumor [10–11]. Although AS1411 induces cytotoxicity on GBM in vitro and in vivo [12], the related mechanisms remain unclear. Understanding the effect of AS1411 on glioma may solve drug resistance of GBM and promote further therapeutic strategies.…”

Section: Introductionmentioning

confidence: 99%

“…It has been found that the main pharmacology of AS1411 is to interfere nucleolin (NCL), a protein that has the ability to bind to G-quadruplex-forming DNA sequences [12]. The expression of NCL is correlated with cell proliferative status and its protein level is being widely used as a bio-marker of cell proliferation; moreover, NCL expression has been shown to associate with the development and progression of various cancers [13].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

View full text Add to dashboard Cite

AS1411 binds nucleolin (NCL) and is the first oligodeoxynucleotide aptamer to reach phase I and II clinical trials for the treatment of several cancers. However, the mechanisms by which AS1411 targets and kills glioma cells and tissues remain unclear. Here we report that AS1411 induces cell apoptosis and cycle arrest, and inhibits cell viability by up-regulation of p53 and down-regulation of Bcl-2 and Akt1 in human glioma cells. NCL was overexpressed in both nucleus and cytoplasm in human glioma U87, U251 and SHG44 cells compared to normal human astrocytes (NHA). AS1411 bound NCL and inhibited the proliferation of glioma cells but not NHA, which was accompanied with up-regulation of p53 and down-regulation of Bcl-2 and Akt1. Moreover, AS1411 treatment resulted in the G2/M cell cycle arrest in glioma cells, which was however abolished by overexpression of NCL. Further, AS1411 induced cell apoptosis, which was prevented by silencing of p53 and overexpression of Bcl-2. In addition, AS1411 inhibited the migration and invasion of glioma cells in an Akt1-dependent manner. Importantly, AS1411 inhibited the growth of glioma xenograft and prolonged the survival time of glioma tumor-bearing mice. These results revealed a promising treatment of glioma by oligodeoxynucleotide aptamer.

show abstract

“…The level of NCL synthesis is correlated with the rate of cell doubling, its expression is thus greater in many tumor cells types [21,22]. NCL is a marker of several human cancer such as colorectal gastric, lung, cervical and breast carcinomas, melanoma and glioblastoma [23][24][25][26][27][28][29][30][31][32][33][34].…”

Section: Ncl: a Promising Target For Cancer Therapymentioning

confidence: 99%

Nanoparticles Functionalized with Ligands of Cell Surface Nucleolin for Cancer Therapy and Diagnosis

Destouches¹

2015

J Nanomed Nanotechnol

View full text Add to dashboard Cite

Conventional cancer chemotherapies are often limited by their non-targeted nature and their inadequate delivery to the tumor affecting the normal tissues and leading to toxic adverse effects. In order to improve the anticancer efficacy and safety of these drugs, as well as the diagnosis capacity of imaging agents, nanoparticles drug delivery system has been developed combining ligands enabling tumor targeting at a cellular level and drug carrier capacity. Nucleolin (NCL) is a multifunctional protein that could shuttle from nucleolus to nucleoplasm, cytoplasm and cell surface. This ribonucleo protein over expressed at the cell surface of cancer cells is involved in many cancer processes supporting tumorigenesis such as cell proliferation and apoptosis. Additionally, NCL expression is enhanced in angiogenic vessels, enabling multi-targeting strategies toward the tumor microenvironment. In this context, several compounds targeting NCL, such as the aptamer AS1411, the peptide F3 and the multivalent pseudopeptide N6L, have been developed and investigated for cancer therapy. Due to their cancer cell targeting capacities, these compounds have been evaluated to mediate highly specific and effective nanoparticles for drug delivery to the tumor. In this report, we present a review of literature focusing on drug-loaded nanoparticles conjugated with these nucleolin ligands, strikingly emphasizing the success of such a strategy.

show abstract

Interfering with the interaction between ErbB1, nucleolin and Ras as a potential treatment for glioblastoma

Cited by 33 publications

References 39 publications

Mechanistic studies of anticancer aptamer AS1411 reveal a novel role for nucleolin in regulating Rac1 activation

Mechanistic studies of anticancer aptamer AS1411 reveal a novel role for nucleolin in regulating Rac1 activation

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

Nanoparticles Functionalized with Ligands of Cell Surface Nucleolin for Cancer Therapy and Diagnosis

Contact Info

Product

Resources

About