ArticleTumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine2012
mTORC1 inhibition and ECM-cell adhesion-independent drug resistance via PI3K-AKT and PI3K-RAS-MAPK feedback loops.
Article in Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 29 citations in OpenAlex.
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- Regulation of mPGES-1 composition and cell growth via the MAPK signaling pathway in jurkat cells.Experimental and therapeutic medicine · 2018Article
- Analysis of IL6-protein complexes in chondrosarcoma.Biomedical reports · 2018Article
- Toll like receptors TLR1/2, TLR6 and MUC5B as binding interaction partners with cytostatic proline rich polypeptide 1 in human chondrosarcoma.International journal of oncology · 2018Article
- Epigenetic control of cancer by neuropeptides.Biomedical reports · 2017Article
- Triptolide exerts pro-apoptotic and cell cycle arrest activity on drug-resistant human lung cancer A549/Taxol cells via modulation of MAPK and PI3K/Akt signaling pathways.Oncology letters · 2016Article
- Effect of cytostatic proline rich polypeptide-1 on tumor suppressors of inflammation pathway signaling in chondrosarcoma.Molecular and clinical oncology · 2016Article
- Article
- Epigenetic regulation of embryonic stem cell marker miR302C in human chondrosarcoma as determinant of antiproliferative activity of proline-rich polypeptide 1.International journal of oncology · 2015Article
- An orthotopic mouse model for chondrosarcoma of bone provides an in vivo tool for drug testing.Virchows Archiv : an international journal of pathology · 2015Article
- Restoration of desmosomal junction protein expression and inhibition of H3K9-specific histone demethylase activity by cytostatic proline-rich polypeptide-1 leads to suppression of tumorigenic potential in human chondrosarcoma cells.Molecular and clinical oncology · 2015Article
- Genome-wide mRNA and miRNA expression data analysis to screen for markers involved in sarcomagenesis in human chondrosarcoma cell lines.Genomics data · 2014Article
- Inhibition of Vav3 could reverse the drug resistance of gastric cancer cells by downregulating JNK signaling pathway.Cancer gene therapy · 2014Article
- AQP5 silencing suppresses p38 MAPK signaling and improves drug resistance in colon cancer cells.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2014Article
- Increased prevalence of eosinophilic gastrointestinal disorders in pediatric PTEN hamartoma tumor syndromes.Journal of pediatric gastroenterology and nutrition · 2014Article
- Regulation of onco and tumor suppressor MiRNAs by mTORC1 inhibitor PRP-1 in human chondrosarcoma.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2014Article
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Authors and funding
3 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mammalian target of rapamycin (mTOR) serine threonine kinase is the enzyme that regulates cancer cell growth by altering nutrient supplies to cancer cells. The neuropeptide (proline-rich peptide 1 (PRP-1)), galarmin, produced by the brain neurosecretory cells is a mTOR kinase inhibitor with powerful 80% antiproliferative cytostatic effect in a high-grade chondosarcoma and other mesenchymal tumors. However, the negative feedback loop of phosphatidylinositol 3 kinase-Protein kinase B (PKB), PI3K-AKT and PI3K-rat sarcoma (RAS)-mitogen-activated protein kinase (MAPK) activation is well documented for mTOR inhibitors. This study explored the involvement of those loops in drug resistance after the treatment with mTOR complex 1 (mTORC1) inhibitor, PRP-1. Multidrug resistance assay (MDR) demonstrated that this cytokine did not inhibit permeability glycoprotein-mediated MDR in chondrosarcoma. Phospho-MAPK array in human chondrosarcoma cell line treated with galarmin (10 μg/ml,) showed a strong upregulation of phosphorylated glycogen synthase kinase 3β (GSK3β) via activation of PI3K-AKT and MAPK feedback loops. Such GSK3β inactivation leads to β-catenin accumulation that entails drug resistance. The ability of cells to metastasize is reflected in their capacity to adhere to extracellular matrix and endothelium. Laminin cell adhesion assay demonstrated that PRP-1 in the same concentrations that inhibit mTOR kinase inhibited JJ012 chondrosarcoma cell adhesion. The neuropeptide did not have any effect on the expression of total focal adhesion kinase and its phosphorylated form. Thus, it was not accompanied by total HAT downregulation and total HDAC upregulation. Combinatorial treatments of PRP-1 with MAPK and PI3K/AKT inhibitors most probably will lead to full cytotoxicity overcoming drug resistance.
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