Dataset Information

P53-Mediated PI3K/AKT/mTOR Pathway Played a Role in PtoxDpt-Induced EMT Inhibition in Liver Cancer Cell Lines.

ABSTRACT: Epithelial-mesenchymal transition (EMT) involves metastasis and drug resistance; thus, a new EMT reversing agent is required. It has shown that wild-type p53 can reverse EMT back to epithelial characteristics, and iron chelator acting as a p53 inducer has been demonstrated. Moreover, recent study revealed that etoposide could also inhibit EMT. Therefore, combination of etoposide with iron chelator might achieve better inhibition of EMT. To this end, we prepared di-2-pyridineketone hydrazone dithiocarbamate S-propionate podophyllotoxin ester (PtoxDpt) that combined the podophyllotoxin (Ptox) structural unit (etoposide) with the dithiocarbamate unit (iron chelator) through the hybridization strategy. The resulting PtoxDpt inherited characteristics from parent structural units, acting as both the p53 inducer and topoisomerase II inhibitor. In addition, the PtoxDpt exhibited significant inhibition in migration and invasion, which correlated with downregulation of matrix metalloproteinase (MMP). More importantly, PtoxDpt could inhibit EMT in the absence or presence of TGF-?1, concomitant to the ROS production, and the additional evidence revealed that PtoxDpt downregulated AKT/mTOR through upregulation of p53, indicating that PtoxDpt induced EMT inhibition through the p53/PI3K/AKT/mTOR pathway.

SUBMITTER: Li Y

PROVIDER: S-EPMC6525883 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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p53-Mediated PI3K/AKT/mTOR Pathway Played a Role in Ptox<sup>Dpt</sup>-Induced EMT Inhibition in Liver Cancer Cell Lines.

Li Yongli Y Wang Tingting T Sun Yanjie Y Huang Tengfei T Li Cuiping C Fu Yun Y Li Yichun Y Li Changzheng C

Oxidative medicine and cellular longevity 20190505

Epithelial-mesenchymal transition (EMT) involves metastasis and drug resistance; thus, a new EMT reversing agent is required. It has shown that wild-type p53 can reverse EMT back to epithelial characteristics, and iron chelator acting as a p53 inducer has been demonstrated. Moreover, recent study revealed that etoposide could also inhibit EMT. Therefore, combination of etoposide with iron chelator might achieve better inhibition of EMT. To this end, we prepared di-2-pyridineketone hydrazone dith ...[more]

PMID: 31191795

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Project description:PurposeBreast cancer (BC), with varying histopathology, biology and response to systemic treatment, is the second leading cause of cancer-related mortality. Previous studies have inferred that the expression of mitochondrial ribosomal proteins (MRPs) is possibly related to the occurrence/progression of BC. MRPL13 might be one of the potential MRP candidates that are involved in BC tumorigenesis, but its role in BC has rarely been reported. The purpose of the current study was to evaluate the prognostic significance of MRPL13, as well as to explore its potential biological functions in BC.Materials and methodsA series of bioinformatic and statistical methods were adopted to assess the MRPL13 expression profile, its relationship with clinicopathological characteristics, copy number variation (CNV), impact on clinical outcomes and relevant functions. All the results are analysed by 1097 BC patients collected from The Cancer Genome Atlas (TCGA) dataset and 52 clinical samples for immunohistochemistry (IHC) assay.ResultsThe results demonstrated that the expression of MRPL13 in BC tissues was remarkably elevated than that in normal breast tissues. In addition, the Kaplan-Meier curves and Cox model indicated that patients with high MRPL13 expression were connected to a worse prognosis, heralding the independent prognostic value of this protein in BC. Moreover, an enrichment analysis showed that MRPL13 was mainly involved in cell cycle/division-related, RNA processing (degradation/splicing), MYC targets and the MTORC1 pathways. In addition, RNA interference (RNAi)-mediated MRPL13 silencing remarkedly inhibited proliferation and migration as well as the expression of EMT-related genes of BC cells in vitro. Mechanistically, attenuation of MRPL13 significantly suppressed the phosphorylation of AKT and mTOR, which could be partially abolished by 740Y-P (a PI3K agonist).ConclusionOur results provide evidence for the first time that increased MRPL13 expression correlates with adverse clinicopathological variables and unfavorable clinical outcomes of BC patients. Knockdown of MRPL13 restrains the proliferation and migration potential and EMT process of BC through inhibiting PI3K/AKT/mTOR signaling pathway.

Dataset Information

P53-Mediated PI3K/AKT/mTOR Pathway Played a Role in PtoxDpt-Induced EMT Inhibition in Liver Cancer Cell Lines.

Publications

p53-Mediated PI3K/AKT/mTOR Pathway Played a Role in Ptox<sup>Dpt</sup>-Induced EMT Inhibition in Liver Cancer Cell Lines.

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