Repression of c-Kit by p53 is mediated by miR-34 and is associated with reduced chemoresistance, migration and stemness

Siemens, Helge; Jackstadt, René; Kaller, Markus; Hermeking, Heiko

doi:10.18632/oncotarget.1202

Cited by 134 publications

(112 citation statements)

References 83 publications

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“…In this study, we unequivocally characterized not only miR-34a but also its target SIRT1 as a determinant player during DCA-induced apoptosis in primary rat hepatocytes. In fact, the functional role and significance of the p53/ miR-34a axis have been expanding in these last years, not only in apoptosis (56) but in cancer as well (57)(58)(59).…”

Section: Discussionmentioning

confidence: 99%

c-Jun N-Terminal Kinase 1/c-Jun Activation of the p53/MicroRNA 34a/Sirtuin 1 Pathway Contributes to Apoptosis Induced by Deoxycholic Acid in Rat Liver

Ferreira

Afonso

Rodrigues

et al. 2014

Molecular and Cellular Biology

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MicroRNAs (miRs) are increasingly associated with metabolic liver diseases. We have shown that ursodeoxycholic acid, a hydrophilic bile acid, counteracts the miR-34a/sirtuin 1 (SIRT1)/p53 pathway, activated in the liver of nonalcoholic steatohepatitis (NASH) patients. In contrast, hydrophobic bile acids, particularly deoxycholic acid (DCA), activate apoptosis and are increased in NASH. We evaluated whether DCA-induced apoptosis of rat hepatocytes occurs via miR-34a-dependent pathways and whether they connect with c-Jun N-terminal kinase (JNK) induction. DCA enhanced miR-34a/SIRT1/p53 proapoptotic signaling in a dose-and time-dependent manner. In turn, miR-34a inhibition and SIRT1 overexpression significantly rescued targeting of the miR-34a pathway and apoptosis by DCA. In addition, p53 overexpression activated the miR-34a/SIRT1/p53 pathway, further induced by DCA. DCA increased p53 expression as well as p53 transcriptional activation of PUMA and miR-34a itself, providing a functional mechanism for miR-34a activation. JNK1 and c-Jun were shown to be major targets of DCA, upstream of p53, in engaging the miR-34a pathway and apoptosis. Finally, activation of this JNK1/miR-34a proapoptotic circuit was also shown to occur in vivo in the rat liver. These results suggest that the JNK1/p53/miR-34a/SIRT1 pathway may represent an attractive pharmacological target for the development of new drugs to arrest metabolism-and apoptosis-related liver pathologies.

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Section: Discussionmentioning

confidence: 99%

c-Jun N-Terminal Kinase 1/c-Jun Activation of the p53/MicroRNA 34a/Sirtuin 1 Pathway Contributes to Apoptosis Induced by Deoxycholic Acid in Rat Liver

Ferreira

Afonso

Rodrigues

et al. 2014

Molecular and Cellular Biology

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“…Real-time Impedance Measurement-Determinations of cellular impedance as a measure of cell proliferation were performed as described previously (39). Twenty-four hours after seeding, DOX was added to the respective wells.…”

Section: Methodsmentioning

confidence: 99%

p53-Regulated Networks of Protein, mRNA, miRNA, and lncRNA Expression Revealed by Integrated Pulsed Stable Isotope Labeling With Amino Acids in Cell Culture (pSILAC) and Next Generation Sequencing (NGS) Analyses

Hünten

Kaller

Drepper

et al. 2015

Molecular & Cellular Proteomics

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We determined the effect of p53 activation on de novo protein synthesis using quantitative proteomics (pulsed stable isotope labeling with amino acids in cell culture/ pSILAC) in the colorectal cancer cell line SW480. This was combined with mRNA and noncoding RNA expression analyses by next generation sequencing (RNA-, miR-Seq). The p53 gene encodes a tumor-suppressive protein, which is activated by DNA damage, but also by other types of cellular stress (1). p53 functions as a transcription factor that regulates the expression of numerous genes, which mediate cell cycle arrest, senescence and apoptosis, or suppress epithelial-mesenchymal-transition (EMT) 1 and metastasis (2-4). p53 is mutated in at least 50% of human cancers with From the ‡Experimental and Molecular Pathology, Institute of Pathology,

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“…MiR-34, a tumor suppressor miRNA family, is considered to be a critical mediator of p53 function [12][13][14] . Several studies have demonstrated its role in resistance or sensitization to anticancer drugs [15,16] . We found two new targets of sirolimus, p21-activated protein kinase 1 (PAK1) and the ABCB1/MDR1 genes.…”

Section: Introductionmentioning

confidence: 99%

Sirolimus induces apoptosis and reverses multidrug resistance in human osteosarcoma cells in vitro via increasing microRNA-34b expression

et al. 2016

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Aim: Multi-drug resistance poses a critical bottleneck in chemotherapy. given the up-regulation of mToR pathway in many chemoresistant cancers, we examined whether sirolimus (rapamycin), a first generation mTOR inhibitor, might induce human osteosarcoma (os) cell apoptosis and increase the sensitivity of os cells to anticancer drugs in vitro. Methods: human os cell line Mg63/aDM was treated with sirolimus alone or in combination with doxorubicin (aDM), gemcitabine (GEM) or methotrexate (MTX). Cell proliferation and apoptosis were detected using CCK-8 assay and flow cytometry, respectively. MiRnas in the cells were analyzed with miRna microarray. The targets of miR-34b were determined based on Targetscan analysis and luciferase reporter assays. The expression of relevant mRna and proteins was measured using qRT-PCR and Western blotting. MiR-34, PaK1 and aBCB1 levels in 40 tissue samples of os patients were analyzed using qRT-PCR and in situ hybridization assays. Results: Sirolimus (1−100 nmol/L) dose-dependently suppressed the cell proliferation (IC 50 =23.97 nmol/L) and induced apoptosis. Sirolimus (10 nmol/L) significantly sensitized the cells to anticancer drugs, leading to decreased IC 50 values of aDM, geM and MTX (from 25.48, 621.41 and 21.72 μmol/L to 4.93, 73.92 and 6.77 μmol/L, respectively). Treatment of with sirolimus increased miR-34b levels by a factor of 7.5 in the cells. upregulation of miR-34b also induced apoptosis and increased the sensitivity of the cells to the anticancer drugs, whereas transfection with miR-34b-aMo, an inhibitor of miR-34b, reversed the anti-proliferation effect of sirolimus. Two key regulators of cell cycle, apoptosis and multiple drug resistance, PaK1 and aBCB1, were demonstrated to be the direct targets of miR-34b. In 40 tissue samples of OS patients, significantly higher miR-34 ISH score and lower PAK5 and ABCB1 scores were detected in the chemo-sensitive group. Conclusion: sirolimus increases the sensitivity of human os cells to anticancer drugs in vitro by up-regulating miR-34b interacting with PaK1 and aBCB1. a low miR-34 level is an indicator of poor prognosis in os patients.

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Repression of c-Kit by p53 is mediated by miR-34 and is associated with reduced chemoresistance, migration and stemness

Cited by 134 publications

References 83 publications

c-Jun N-Terminal Kinase 1/c-Jun Activation of the p53/MicroRNA 34a/Sirtuin 1 Pathway Contributes to Apoptosis Induced by Deoxycholic Acid in Rat Liver

c-Jun N-Terminal Kinase 1/c-Jun Activation of the p53/MicroRNA 34a/Sirtuin 1 Pathway Contributes to Apoptosis Induced by Deoxycholic Acid in Rat Liver

p53-Regulated Networks of Protein, mRNA, miRNA, and lncRNA Expression Revealed by Integrated Pulsed Stable Isotope Labeling With Amino Acids in Cell Culture (pSILAC) and Next Generation Sequencing (NGS) Analyses

Sirolimus induces apoptosis and reverses multidrug resistance in human osteosarcoma cells in vitro via increasing microRNA-34b expression

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