scholarly journals Akt Inhibition Enhanced the Growth Inhibition Effects of Low-Dose Heavy-Ion Radiation via the PI3K/Akt/p53 Signaling Pathway in C6 Glioblastoma Cells

2021 ◽  
Vol 11 ◽  
Author(s):  
Ke Huang ◽  
Wei Zhao ◽  
Xuqiao Wang ◽  
Yingfei Qiu ◽  
Zelin Liu ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
Signaling Pathway ◽  
Low Dose ◽  
Ion Irradiation ◽  
Heavy Ion ◽  
C6 Cells ◽  
Carbon Ion ◽  
P53 Signaling ◽  
Heavy Ion Radiation ◽  
P53 Signaling Pathway

BackgroundGlioma has one of the highest mortality rates of all tumors of the nervous system and commonly used treatments almost always fail to achieve tumor control. Low-dose carbon-ion radiation can effectively target cancer and tumor cells, but the mechanisms of growth inhibition induced by heavy-ion radiation via the PI3K/Akt signaling pathway are unknown, and inhibition by heavy-ion radiation is minor in C6 cells.MethodsCarbon-ion radiation was used to investigate the effects of heavy-ion radiation on C6 cells, and suppression of Akt was performed using perifosine. MTT assays were used to investigate optimal perifosine treatment concentrations. Clone formation assays were used to investigate the growth inhibition effects of carbon-ion radiation and the effects of radiation with Akt inhibition. Lactate dehydrogenase release, superoxide dismutase activity, and malondialdehyde content were assessed to investigate oxidative stress levels. Expression levels of proteins in the PI3K/Akt/p53 signaling pathway were assessed via western blotting.ResultsThe 10% maximum inhibitory concentration of perifosine was 19.95 μM. In clone formation assays there was no significant inhibition of cell growth after treatment with heavy-ion irradiation, whereas perifosine enhanced inhibition. Heavy-ion radiation induced lactate dehydrogenase release, increased the level of malondialdehyde, and reduced superoxide dismutase activity. Akt inhibition promoted these processes. Heavy-ion radiation treatment downregulated Akt expression, and upregulated B-cell lymphoma-2 (Bcl-2) expression. p53 and Bcl-2 expression were significantly upregulated, and Bcl-2-associated X protein (Bax) expression was downregulated. The expression profiles of pAkt, Bcl-2, and Bax were reversed by perifosine treatment. Caspase 3 expression was upregulated in all radiation groups.ConclusionsThe growth inhibition effects of low-dose heavy-ion irradiation were not substantial in C6 cells, and Akt inhibition induced by perifosine enhanced the growth inhibition effects via proliferation inhibition, apoptosis, and oxidative stress. Akt inhibition enhanced the effects of heavy-ion radiation, and the PI3K/Akt/p53 signaling pathway may be a critical component involved in the process.

Low-dose mithramycin exerts its anticancer effect via the p53 signaling pathway and synergizes with nutlin-3 in gynecologic cancers

2010 ◽  
Vol 101 (6) ◽  
pp. 1387-1395 ◽  
Author(s):  
Tatsuhiro Ohgami ◽  
Kiyoko Kato ◽  
Hiroaki Kobayashi ◽  
Kenzo Sonoda ◽  
Takafumi Inoue ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Low Dose ◽  
Anticancer Effect ◽  
Gynecologic Cancers ◽  
P53 Signaling ◽  
P53 Signaling Pathway

The Molecular Docking of Flavonoids Isolated from Daucus carota as a Dual Inhibitor of MDM2 and MDMX

2020 ◽  
Vol 15 (2) ◽  
pp. 154-164 ◽  
Author(s):  
Ijaz Muhammad ◽  
Noor Rahman ◽  
Gul E. Nayab ◽  
Sadaf Niaz ◽  
Mohibullah Shah ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Cancer Therapy ◽  
Natural Product ◽  
Signaling Pathway ◽  
In Silico ◽  
P53 Protein ◽  
Dual Inhibitor ◽  
P53 Signaling ◽  
In Silico Studies ◽  
P53 Signaling Pathway

Background: Cancer is characterized by overexpression of p53 associated proteins, which down-regulate P53 signaling pathway. In cancer therapy, p53 activity can be restored by inhibiting the interaction of MDMX (2N0W) and MDM2 (4JGR) proteins with P53 protein. Objective: In the current, study in silico approaches were adapted to use a natural product as a source of cancer therapy. Methods: In the current study in silico approaches were adapted to use a natural product as a source of cancer therapy. For in silico studies, Chemdraw and Molecular Operating Environment were used for structure drawing and molecular docking, respectively. Flavonoids isolated from D. carota were docked with cancerous proteins. Result: Based on the docking score analysis, we found that compound 7 was the potent inhibitor of both cancerous proteins and can be used as a potent molecule for inhibition of 2N0W and 4JGR interaction with p53. Conclusion: Thus the compound 7 can be used for the revival of p53 signaling pathway function however, intensive in vitro and in vivo experiments are required to prove the in silico analysis.

scholarly journals Protective Effects of L-Theanine on IPEC-J2 Cells Growth Inhibition Induced by Dextran Sulfate Sodium Via p53 Signaling Pathway

Molecules ◽  
2021 ◽  
Vol 26 (22) ◽  
pp. 7002
Author(s):  
Longlin Zhang ◽  
Mengmeng Ma ◽  
Zhengyi Li ◽  
Haihan Zhang ◽  
Xi He ◽  
...  
Keyword(s):  
Amino Acid ◽  
Signaling Pathway ◽  
Dextran Sulfate ◽  
Dextran Sulfate Sodium ◽  
Nucleotide Metabolism ◽  
Normal Operation ◽  
Protective Effects ◽  
P53 Signaling ◽  
P53 Signaling Pathway

L-theanine is a nonprotein amino acid found in tea leaves and has been widely used as a safe food additive in beverages or foods because of its varied bioactivities. The aim of this study was to reveal the in vitro gastrointestinal protective effects of L-theanine in DSS-induced intestinal porcine enterocyte (IPEC-J2) cell models using molecular and metabolic methods. Results showed that 2.5% dextran sulfate sodium (DSS) treatment inhibited the cell proliferation of IPEC-J2 and blocked the normal operation of the cell cycle, while L-theanine pretreatment significantly preserved these trends to exert protective effects. L-theanine pre-treatment also up-regulated the EGF, CDC2, FGF2, Rb genes and down-regulated p53, p21 proliferation-related mRNA expression in DSS-treated cells, in accompany with p53 signaling pathway inhibition. Meanwhile, metabolomics analysis revealed that L-theanine and DSS treated IPEC-J2 cells have different metabolomic profiles, with significant changes in the key metabolites involved in pyrimidine metabolism and amino acid metabolism, which play an important role in nucleotide metabolism. In summary, L-theanine has a beneficial protection in DSS-induced IPEC-J2 cells via promoting proliferation and regulating metabolism disorders.

p53 signaling pathway polymorphisms, cancer risk and tumor phenotype in TP53 R337H mutation carriers

2017 ◽  
Vol 17 (2) ◽  
pp. 269-274 ◽  
Author(s):  
Gabriel S. Macedo ◽  
Igor Araujo Vieira ◽  
Fernanda Salles Luiz Vianna ◽  
Barbara Alemar ◽  
Juliana Giacomazzi ◽  
...  
Keyword(s):  
Cancer Risk ◽  
Signaling Pathway ◽  
P53 Signaling ◽  
Mutation Carriers ◽  
Tumor Phenotype ◽  
P53 Signaling Pathway

scholarly journals N-α-Acetyltransferase 10 protein inhibits invasion and metastasis of oral squamous cell carcinoma via regulating Pirh2-p53 signaling pathway

2020 ◽  
Author(s):  
Fazhan Wang ◽  
Jun Zheng ◽  
Yongyong Yang ◽  
Jie Yang ◽  
Ting Luo ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Oral Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Signaling Pathway ◽  
Squamous Cell ◽  
Nude Mice ◽  
Invasion And Metastasis ◽  
P53 Signaling ◽  
P53 Signaling Pathway

Abstract Background Naa10p (N-α-Acetyltransferase 10 protein) was reported to be involved in tumor invasion and metastasis in several of tumors. However, the role and mechanism of Naa10p mediated invasion and metastasis in oral squamous cell carcinoma (OSCC) remains undetermined. Methods The functional role of Naa10p in OSCC cells were determined using Transwell assay in vitro and xenograft tumorigenesis in nude mice. Immunoprecipitation, GST-pull down assays and immunofluorescence were performed to confirm the interaction between Naa10p and RelA/p65 in OSCC cells. Lastly, luciferase reporter assays, chromatin immunoprecipitation (ChIP) and western blot were used to evalute the effect of Naa10p expression on the Pirh2-p53 signaling pathway. Results Naa10p inhibits cell migration and invasion in vitro and attenuates the xenograft tumorigenesis in nude mice. Mechanistically, there is a physical interaction between Naa10p and RelA/p65 in OSCC cells, thereby preventing RelA/p65-mediated transcriptional activation of Pirh2. Consequently, inhibition of Pirh2 increased p53 level and suppressed the expression of p53 downstream targets, MMP-2 and MMP-9. Conclusion Naa10p function as a tumor metastasis suppressor in the progression of OSCC by targeting Pirh2-p53 axis, and might be a prognostic marker as well as a therapeutic target for OSCC.

Application of minimal mathematical models for the dynamics of the signaling pathway of the p53 - miRNA to the analysis of laboratory data

2021 ◽  
pp. 4-49
Author(s):  
Софья Дмитриевна Сенотрусова ◽  
Ольга Фалалеевна Воропаева ◽  
Юрий Иванович Шокин
Keyword(s):  
Mathematical Models ◽  
Signaling Pathway ◽  
Numerical Solutions ◽  
Laboratory Data ◽  
Minimal Models ◽  
Basic Model ◽  
P53 Signaling ◽  
Wide Range ◽  
P53 Signaling Pathway

Работа посвящена практическому использованию минимальных математических моделей динамики сигнального пути p53 для описания достаточно широкого круга лабораторных экспериментов, в которых взаимодействие p53 и белковингибиторов p53 опосредуется микроРНК, образующими с p53 петлю положительной обратной связи. Представлены базовая модель, разработанные на ее основе новые минимальные модели, алгоритм численного решения прямых и обратных коэффициентных задач и результаты сопоставления полученных численных решений с экспериментальными данными о динамике уровней белков p53, p21, Bax, белков-ингибиторов Mdm2, Wip1, Sirt1 и различных микроРНК (miR-16, miR-34a, miR-192, miR-194, miR-215) в условиях стрессовых воздействий. С привлечением полученных математических моделей исследованы базовые механизмы функционирования сигнального пути p53 в условиях, приближенных к условиям конкретных лабораторных экспериментов in vitro и in vivo. Продемонстрированы синергический эффект гиперактивации сигнального пути p53, в котором задействованы микроРНК, и механизмы бимодального переключения. Показана ключевая роль p53-зависимых микроРНК в реализации некоторых гипотетических терапевтических стратегий, связанных с управлением механизмом активации апоптоза клеток. В рамках принятой базовой модели даны оценки вероятности рассогласования в диагностике дегенеративных заболеваний, основанной на анализе уровня p53зависимых микроРНК и p53, при слабой и умеренной дерегуляции микроРНК. This study addresses the practical use of minimal mathematical models of the dynamics of a hypothetical system of the p53 signaling pathway to describe a fairly wide range of laboratory experiments. In such system, the interaction of p53 and p53 inhibitor proteins is mediated by microRNAs that form a positive feedback loop with p53. A basic model, new minimal models developed on its basis, an algorithm for the numerical solution of direct and inverse coefficient problems, and the results of comparing the obtained numerical solutions with experimental data on the dynamics of the levels of p53, p21, Bax proteins, inhibitor proteins Mdm2, Wip1, Sirt1, and various microRNAs (miR-16, miR-34a, miR-192, miR-194, miR-215) under stress conditions are presented. In numerical experiments, the main mechanisms of the p53 signaling pathway were investigated. A synergistic effect of hyperactivation of the p53 signaling pathway and bimodal switching mechanisms has been demonstrated. We show the key role of p53-dependent microRNAs in the implementation of some hypothetical therapeutic strategies associated with the control mechanism for activation of cells apoptosis. Within the framework of the accepted basic model, we estimated the probability of mismatch in the diagnosis of the patient’s status. The status is based on the analysis of the level of p53-dependent microRNAs and p53, with weak and moderate deregulation of microRNAs.

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