Nucleolin aptamer N6L reprograms the translational machinery and acts synergistically with mTORi to inhibit pancreatic cancer proliferation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA766664 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16089500.fastq.gz | Fastqsanger.gz | |||
| SRR16089501.fastq.gz | Fastqsanger.gz | |||
| SRR16089502.fastq.gz | Fastqsanger.gz | |||
| SRR16089503.fastq.gz | Fastqsanger.gz | |||
| SRR16089504.fastq.gz | Fastqsanger.gz |
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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
Project description: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.
| S-EPMC8508287 | biostudies-literature
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.
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Project description:The experiments were carried out to map the ligand binding landscape of various DNA and RNA duplexed aptamer families. Duplexed Aptamer (DA) constructs were engineered from (i) natural and synthetic DNA and RNA aptamers and (i) synthetic oligonucleotide aptamer-complementary elements synthesized on custom DNA microarrays. The aptamers tested consist of the ATP DNA aptamer, the ATP RNA aptamer, the cocaine DNA aptamer, the human alpha-thrombin DNA aptamer, and the natural add riboswitch aptamer from the pathogenic bacteria Vibrio vulnificus. Each duplexed aptamer family consists of 1000's of synthetic constructs, each formed by hybridizing the aptamer with an aptamer-complementary element (ACE) - here, ACEs consisted of various DNA oligonucleotides synthesized as a custom DNA microarray.
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Project description:The experiments were carried out to map the ligand binding landscape of various DNA and RNA duplexed aptamer families. Duplexed Aptamer (DA) constructs were engineered from (i) natural and synthetic DNA and RNA aptamers and (i) synthetic oligonucleotide aptamer-complementary elements synthesized on custom DNA microarrays. The aptamers tested consist of the ATP DNA aptamer, the ATP RNA aptamer, the cocaine DNA aptamer, the human alpha-thrombin DNA aptamer, and the natural add riboswitch aptamer from the pathogenic bacteria Vibrio vulnificus. Each duplexed aptamer family consists of 1000's of synthetic constructs, each formed by hybridizing the aptamer with an aptamer-complementary element (ACE) - here, ACEs consisted of various DNA oligonucleotides synthesized as a custom DNA microarray.
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Project description:The experiments were carried out to map the ligand binding landscape of various DNA and RNA duplexed aptamer families. Duplexed Aptamer (DA) constructs were engineered from (i) natural and synthetic DNA and RNA aptamers and (i) synthetic oligonucleotide aptamer-complementary elements synthesized on custom DNA microarrays. The aptamers tested consist of the ATP DNA aptamer, the ATP RNA aptamer, the cocaine DNA aptamer, the human alpha-thrombin DNA aptamer, and the natural add riboswitch aptamer from the pathogenic bacteria Vibrio vulnificus. Each duplexed aptamer family consists of 1000's of synthetic constructs, each formed by hybridizing the aptamer with an aptamer-complementary element (ACE) - here, ACEs consisted of various DNA oligonucleotides synthesized as a custom DNA microarray.
2017-12-20 | E-MTAB-6376 | biostudies-arrayexpress
Project description:The experiments were carried out to map the ligand binding landscape of various DNA and RNA duplexed aptamer families. Duplexed Aptamer (DA) constructs were engineered from (i) natural and synthetic DNA and RNA aptamers and (i) synthetic oligonucleotide aptamer-complementary elements synthesized on custom DNA microarrays. The aptamers tested consist of the ATP DNA aptamer, the ATP RNA aptamer, the cocaine DNA aptamer, the human alpha-thrombin DNA aptamer, and the natural add riboswitch aptamer from the pathogenic bacteria Vibrio vulnificus. Each duplexed aptamer family consists of 1000's of synthetic constructs, each formed by hybridizing the aptamer with an aptamer-complementary element (ACE) - here, ACEs consisted of various DNA oligonucleotides synthesized as a custom DNA microarray.
2017-12-20 | E-MTAB-6374 | biostudies-arrayexpress
Project description:To further explore the function and underlying mechanism of nucleolin in embryonic stem cells (ESCs), we compared the transcription profile of tetracycline (Tc)-inducible EGFP (as a control) or nucleolin siRNA expression-stable ESCs cultured with or without Tc for 3 days, and identified distinct classes of up- and down-regulated genes by nucleolin in mouse ESCs. Total RNA obtained from CGR8 ES cells stably integrated with Tc-inducible siRNA EGFP, nucleoin-1 or nucleolin-2 cultured with or without Tc for 3 days, and then hybridized to Illumina Sentrix Mouse-6 v2.0 BeadChips. Three replicates each condition.
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Project description:Although Rrp6 contains a helicase and RNase D domain at the C-terminus, it is not involved in stable RNA interactions. We thus hypothesized that mRrp6-mediated nucleolar inflammatory RNA degradation may depend on the pre-mRNA substrate that is delivered to the mRrp6-exosome complex by nucleolin as a guide factor. To demonstrate this possibility, we examined nucleoplasmic RNAs which were bound to nucleolin through RNA-IP-sequencing at the late time points of LPS stimulation.
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