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Nucleolin Aptamer N6L Reprograms the Translational Machinery and Acts Synergistically with mTORi to Inhibit Pancreatic Cancer Proliferation.

ABSTRACT: We previously showed that N6L, a pseudopeptide that targets nucleolin, impairs pancreatic ductal adenocarcinoma (PDAC) growth and normalizes tumor vessels in animal models. In this study, we analyzed the translatome of PDAC cells treated with N6L to identify the pathways that were either repressed or activated. We observed a strong decrease in global protein synthesis. However, about 6% of the mRNAs were enriched in the polysomes. We identified a 5'TOP motif in many of these mRNAs and demonstrated that a chimeric RNA bearing a 5'TOP motif was up-regulated by N6L. We demonstrated that N6L activates the mTOR pathway, which is required for the translation of these mRNAs. An inhibitory synergistic effect in PDAC cell lines, including patient-derived xenografts and tumor-derived organoids, was observed when N6L was combined with mTOR inhibitors. In conclusion, N6L reduces pancreatic cells proliferation, which then undergoes translational reprogramming through activation of the mTOR pathway. N6L and mTOR inhibitors act synergistically to inhibit the proliferation of PDAC and human PDX cell lines. This combotherapy of N6L and mTOR inhibitors could constitute a promising alternative to treat pancreatic cancer.

SUBMITTER: Chalabi-Dchar M

PROVIDER: S-EPMC8508287 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Nucleolin aptamer N6L reprograms the translational machinery and acts synergistically with mTORi to inhibit pancreatic cancer proliferation

Project description:We previously showed that N6L, a pseudo-peptide that targets nucleolin, impairs pancreatic ductal adenocarcinoma (PDAC) growth and normalizes tumor vessels in animal models. In this study, we analyzed the translatome of PDAC cells treated with N6L to identify the pathways that were either repressed or activated. We observed a strong decrease of global protein synthesis. However, about 6% of the mRNAs were enriched in the polysomes. We identified a 5’TOP motif in many of these mRNAs, and demonstrated that a chimeric RNA bearing a 5‘TOP motif was up-regulated by N6L. We demonstrated that N6L activates the mTOR pathway which is required for the translation of these mRNAs. An inhibitory synergistic effect in PDAC cell lines including patient derived-xenografts and tumor derived-organoids was observed when N6L was combined with mTOR inhibitors. In conclusion, N6L reduces pancreatic cells proliferation which then undergoes a translational reprogramming through activation of the mTOR pathway. N6L and mTOR inhibitors act synergistically to inhibit the proliferation of PDAC and human PDX cell lines. This combotherapy of N6L and mTOR inhibitors could constitute a promising alternative to treat pancreatic cancer.

2021-10-20 | GSE184857 | GEO

Nucleolin aptamer N6L reprograms the translational machinery and acts synergistically with mTORi to inhibit pancreatic cancer proliferation

Project description:Nucleolin aptamer N6L reprograms the translational machinery and acts synergistically with mTORi to inhibit pancreatic cancer proliferation

| PRJNA766664 | ENA

Nucleolin Overexpression Confers Increased Sensitivity to the Anti-Nucleolin Aptamer, AS1411.

Project description:AS1411 is an antiproliferative DNA aptamer, which binds the ubiquitous protein, nucleolin. In this study, we show that constitutive overexpression of nucleolin confers increased sensitivity to the growth inhibitory effects of AS1411. HeLa cells overexpressing nucleolin have an increased growth rate and invasiveness relative to control cells. Nucleolin overexpressing cells demonstrate increased growth inhibition in response to the AS1411 treatment, which correlates with increased apoptosis and cell cycle arrest, when compared to non-transfected cells. AS1411 induces nucleolin expression at the RNA and protein level in HeLa cells, suggesting a feedback loop with important implications for the clinical use of AS1411.

| S-EPMC6396827 | biostudies-literature

Anti-nucleolin aptamer AS1411: an advancing therapeutic.

Project description:Targeted therapy is highly desirable, as it allows for selective cytotoxicity on diseased cells without off-target side effects. Nucleolin is a remarkable target for cancer therapy given its high abundance, selective presence on the plasma membrane, and multifaceted influence on the initiation and progression of cancer. Nucleolin is a protein overexpressed on the cell membrane in many tumors and serves as a binding protein for several ligands implicated in angiogenesis and tumorigenesis. Nucleolin is present in the cytoplasm, nucleoplasm, and nucleolus and is used by selected pathogens for cell entry. AS1411 is a guanosine-rich oligonucleotide aptamer that binds nucleolin and is internalized in the tumor cells. AS1411 is well tolerated at therapeutic doses and localizes to tumor cells overexpressing nucleolin. AS1411 has a good safety profile with efficacy in relapsed acute myeloid leukemia and renal cell carcinoma producing mild or moderate side effects. The promising potential of AS1411 is its ability to be conjugated to drugs and nanoparticles. When a drug is bound to AS1411, the drug will localize to tumor cells leading to targeted therapy with fewer systemic side effects than traditional practices. AS1411 can also be bound to nanoparticles capable of detecting nucleolin at concentrations far lower than lab techniques used today for cancer diagnosis. AS1411 has a promising potential to change cancer diagnoses and treatment.

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ATRA mechanically reprograms pancreatic stellate cells to suppress matrix remodelling and inhibit cancer cell invasion.

Project description:Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a dismal survival rate. Persistent activation of pancreatic stellate cells (PSCs) can perturb the biomechanical homoeostasis of the tumour microenvironment to favour cancer cell invasion. Here we report that ATRA, an active metabolite of vitamin A, restores mechanical quiescence in PSCs via a mechanism involving a retinoic acid receptor beta (RAR-β)-dependent downregulation of actomyosin (MLC-2) contractility. We show that ATRA reduces the ability of PSCs to generate high traction forces and adapt to extracellular mechanical cues (mechanosensing), as well as suppresses force-mediated extracellular matrix remodelling to inhibit local cancer cell invasion in 3D organotypic models. Our findings implicate a RAR-β/MLC-2 pathway in peritumoural stromal remodelling and mechanosensory-driven activation of PSCs, and further suggest that mechanical reprogramming of PSCs with retinoic acid derivatives might be a viable alternative to stromal ablation strategies for the treatment of PDAC.

| S-EPMC5023948 | biostudies-literature

ORESARA15 Acts Synergistically with ANGUSTIFOLIA3 and Separately from AINTEGUMENTA to Promote Cell Proliferation during Leaf Growth.

Project description:Developing leaves undergo sequential coordinated cell proliferation and cell expansion to determine their final size and shape. Although several important regulators of cell proliferation have been reported, the gene network regulating leaf developmental processes remains unclear. Previously, we showed that ORESARA15 (ORE15) positively regulates the rate and duration of cell proliferation by promoting the expression of direct targets, GROWTH-REGULATING FACTOR (GRF) transcription factors, during leaf growth. In the current study, we examined the spatiotemporal patterns of ORE15 expression and determined that ORE15 expression partially overlapped with AN3/GIF1 and ANT expression along the midvein in the proximal region of the leaf blade in young leaves. Genetic analysis revealed that ORE15 may function synergistically with AN3 to control leaf growth as a positive regulator of cell proliferation. Our molecular and genetic studies are the first to suggest the importance of functional redundancies between ORE15 and AN3, and between AN3 and ANT in cell proliferation regulatory pathway during leaf growth.

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Intracellular Ca2+ and phorbol esters synergistically inhibit internalization of epidermal growth factor in pancreatic acini.

Project description:The association of 125I-labelled epidermal growth factor (125I-EGF) with mouse pancreatic acinar cells was inhibited by secretagogues which increase intracellular free Ca2+ concentrations. These agents included cholecystokinin-octapeptide (CCK8) and the Ca2+ ionophore A23187. Inhibition by CCK8 was blocked by lowering the incubation temperature from 37 degrees C to 15 degrees C. Moreover, in contrast with studies of intact acini, the binding of 125I-EGF to isolated acinar membrane particles was not affected either by CCK8, or by varying the level of Ca2+ in the incubation medium. These results indicated, therefore, that the inhibition of 125I-EGF association with acinar cells required intact cells that are metabolically active. Since intact cells at 37 degrees C are known to internalize bound EGF rapidly, acid washing was used to distinguish membrane-associated hormone from internalized hormone. Under steady-state conditions 86% of the 125I-EGF associated with the acini was found to be internalized by this technique. When agents that increased intracellular Ca2+ were tested they all markedly reduced the amount of internalized hormone, whereas surface binding was only minimally affected. The phorbol ester 12-O-tetradecanoyl-phorbol 13-acetate (TPA), which is known to activate protein kinase C, a Ca2+-regulated enzyme, also inhibited the association of EGF with acini. This inhibition was similar to that induced by elevated intracellular Ca2+. To test whether these two inhibitory phenomena were related, the effects of TPA in combination with the Ca2+ ionophore A23187 were examined. At low concentrations the effects were synergistic, whereas at high concentrations the maximal level of inhibition was not changed. We suggest therefore that elevated intracellular Ca2+ and phorbol esters may inhibit EGF internalization by a mechanism involving activation of protein kinase C.

| S-EPMC1144377 | biostudies-other

Pax4 synergistically acts with Pdx1, Ngn3 and MafA to induce HuMSCs to differentiate into functional pancreatic ?-cells.

Project description:It has been indicated that the combination of pancreatic and duodenal homeobox 1 (Pdx1), MAF bZIP transcription factor A (MafA) and neurogenin 3 (Ngn3) was able to reprogram various cell types towards pancreatic ?-like cells (p?LCs). Paired box 4 (Pax4), a transcription factor, has a key role in regulating the maturation of pancreatic ?-cells (p?Cs). In the present study, it was investigated whether Pax4 is able to synergistically act with Pdx1, Ngn3 and MafA to induce human umbilical cord mesenchymal stem cells (HuMSCs) to differentiate into functional p?Cs in vitro. HuMSCs were isolated, cultured and separately transfected with adenovirus (Ad) expressing enhanced green fluorescence protein, Pax4 (Ad-Pax4), Pdx1+MafA+Ngn3 (Ad-3F) or Ad-Pxa4 + Ad-3F. The expression of C-peptide, insulin and glucagon was detected by immunofluorescence. The transcription of a panel of genes was determined by reverse transcription-quantitative PCR, including glucagon (GCG), insulin (INS), NK6 homeobox 1 (NKX6-1), solute carrier family 2 member 2 (SLC2A2), glucokinase (GCK), proprotein convertase subtilisin/kexin type 1 (PCSK1), neuronal differentiation 1 (NEUROD1), ISL LIM homeobox 1 (ISL 1), Pax6 and PCSK type 2 (PCSK2). Insulin secretion stimulated by glucose was determined using ELISA. The results suggested that, compared with Ad-3F alone, cells co-transfected with Ad-Pax4 and Ad-3F expressed higher levels of INS and C-peptide, as well as genes expressed in pancreatic ? precursor cells, and secreted more insulin in response to high glucose. Furthermore, the expression of GCG in cells transfected with Ad-3F was depressed by Ad-Pax4. The present study demonstrated that Pax4 was able to synergistically act with the transcription factors Pdx1, Ngn3 and MafA to convert HuMSCs to functional p?LCs. HuMSCs may be potential seed cells for generating functional p?LCs in the therapy of diabetes.

| S-EPMC6755441 | biostudies-literature

Nucleolin-aptamer therapy in retinoblastoma: molecular changes and mass spectrometry–based imaging

Project description:Retinoblastoma (RB) is an intraocular childhood tumor which, if left untreated, leads to blindness and mortality. Nucleolin (NCL) protein which is differentially expressed on the tumor cell surface, binds ligands and regulates carcinogenesis and angiogenesis. We found that NCL is over expressed in RB tumor tissues and cell lines compared to normal retina. We studied the effect of nucleolin-aptamer (NCL-APT) to reduce proliferation in RB tumor cells. Aptamer treatment on the RB cell lines (Y79 and WERI-Rb1) led to significant inhibition of cell proliferation. Locked nucleic acid (LNA) modified NCL-APT administered subcutaneously (s.c.) near tumor or intraperitoneally (i.p.) in Y79 xenografted nude mice resulted in 26 and 65% of tumor growth inhibition, respectively. Downregulation of inhibitor of apoptosis proteins, tumor miRNA-18a, altered serum cytokines, and serum miRNA-18a levels were observed upon NCL-APT treatment. Desorption electrospray ionization mass spectrometry (DESI MS)-based imaging of cell lines and tumor tissues revealed changes in phosphatidylcholines levels upon treatment. Thus, our study provides proof of concept illustrating NCL-APT-based targeted therapeutic strategy and use of DESI MS-based lipid imaging in monitoring therapeutic responses in RB.

2016-11-15 | GSE89818 | GEO

Nucleolin Therapeutic Targeting Decreases Pancreatic Cancer Immunosuppression.

Project description:BackgroundThe pancreatic ductal adenocarcinoma (PDAC) microenvironment is highly fibrotic and hypoxic, with poor immune cell infiltration. Recently, we showed that nucleolin (NCL) inhibition normalizes tumour vessels and impairs PDAC growth.MethodsImmunocompetent mouse models of PDAC were treated by the pseudopeptide N6L,&nbsp;which selectively inhibits NCL. Tumour-infiltrating immune cells and changes in the tumour microenvironment were analysed.ResultsN6L reduced the proportion of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) and increased tumour-infiltrated T lymphocytes (TILs) with an activated phenotype. Low-dose anti-VEGFR2 treatment normalized PDAC vessels but did not modulate the immune suppressive microenvironment. RNAseq analysis of N6L-treated PDAC tumours revealed a reduction of cancer-associated fibroblast (CAF) expansion in vivo and in vitro. Notably, N6L treatment decreased IL-6 levels both in tumour tissues and in serum. Treating mPDAC by an antibody blocking IL-6 reduced the proportion of Tregs and MDSCs and increased the amount of TILs, thus mimicking the effects of N6L.ConclusionsThese results demonstrate that NCL inhibition blocks the amplification of lymphoid and myeloid immunosuppressive cells and promotes T cell activation in PDAC through a new mechanism of action dependent on the direct inhibition of the tumoral stroma.

| S-EPMC9454580 | biostudies-literature

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