scholarly journals Biological Heterogeneity of Chondrosarcoma: From (Epi) Genetics through Stemness and Deregulated Signaling to Immunophenotype

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1317
Author(s):  
Agnieszka Zając ◽  
Sylwia K. Król ◽  
Piotr Rutkowski ◽  
Anna M. Czarnecka
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Point Mutations ◽  
Phosphatidylinositol 3 Kinase ◽  
Chondrocyte Proliferation ◽  
Current State ◽  
P16 Ink4a ◽  
Biological Heterogeneity ◽  
Cellular Markers ◽  
Mdm2 Amplification ◽  
Gene Alterations

Chondrosarcoma (ChS) is a primary malignant bone tumor. Due to its heterogeneity in clinical outcomes and resistance to chemo- and radiotherapies, there is a need to develop new potential therapies and molecular targets of drugs. Many genes and pathways are involved in in ChS progression. The most frequently mutated genes are isocitrate dehydrogenase ½ (IDH1/2), collagen type II alpha 1 chain (COL2A1), and TP53. Besides the point mutations in ChS, chromosomal aberrations, such as 12q13 (MDM2) amplification, the loss of 9p21 (CDKN21/p16/INK4A and INK4A-p14ARF), and several gene fusions, commonly occurring in sarcomas, have been found. ChS involves the hypermethylation of histone H3 and the decreased methylation of some transcription factors. In ChS progression, changes in the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K–AKT–mTOR) and hedgehog pathways are known to play a role in tumor growth and chondrocyte proliferation. Due to recent discoveries regarding the potential of immunotherapy in many cancers, in this review we summarize the current state of knowledge concerning cellular markers of ChS and tumor-associated immune cells. This review compares the latest discoveries in ChS biology from gene alterations to specific cellular markers, including advanced molecular pathways and tumor microenvironment, which can help in discovering new potential checkpoints in inhibitory therapy.

scholarly journals Antihepatocarcinoma Effect of Portulaca oleracea L. in Mice by PI3K/Akt/mTOR and Nrf2/HO-1/NF-κB Pathway

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Zheng Guoyin ◽  
Peng Hao ◽  
Li Min ◽  
Gu Wei ◽  
Chen Zhe ◽  
...  
Keyword(s):  
Nuclear Factor Kappa B ◽  
Mammalian Target Of Rapamycin ◽  
Portulaca Oleracea ◽  
Control Group ◽  
Related Factor ◽  
Protective Effects ◽  
Phosphatidylinositol 3 Kinase ◽  
Pathological Alteration ◽  
Hepatocellular Carcinomas ◽  
Necrosis Factor

The purpose of the present study was to evaluate the pharmacological effects of Portulaca oleracea L. (Purslane) (PL) on N-nitrosodiethylamine- (NDEA-) induced hepatocellular carcinomas (HCC) and explore its potential mechanism. Mice were randomly assigned to four groups: control group, NDEA group, NDEA + Purslane (100 mg/kg) group, and NDEA + Purslane (200 mg/kg) group. The animal of each group was given NDEA (100 ppm) in drinking water. 1 h later, Purslane dissolved in PBS was intragastrically administered for continuous seven days. The results showed that Purslane reduced the activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in liver and serum. Purslane also reduced the contents of interleukin-6 (IL-6), IL-1β, tumor necrosis factor-α (TNF-α), and methane dicarboxylic aldehyde (MDA) and restored the activity of superoxygen dehydrogenises (SOD) in serum. Purslane could obviously attenuate the hepatic pathological alteration. Furthermore, treatment with Purslane effectively inhibited the phosphorylations of phosphatidylinositol 3 kinase (PI3K), protein kinase B (Akt), mammalian target of rapamycin (mTOR), nuclear factor-kappa B (NF-κB), and inhibitor of NF-κBα (IκBα) and upregulated the expressions of NF-E2-related factor 2 (Nrf2) and heme oxygenase- (HO-) 1. In conclusion, our research suggested that Purslane exhibited protective effects on NDEA-induced hepatocellular carcinomas by anti-inflammatory and antioxidative properties via the PI3K/Akt/mTOR and Nrf2/HO-1/NF-κB pathway.

scholarly journals Leptin Induces Macrophage Lipid Body Formation by a Phosphatidylinositol 3-Kinase- and Mammalian Target of Rapamycin-dependent Mechanism

2007 ◽  
Vol 283 (4) ◽  
pp. 2203-2210 ◽  
Author(s):  
Clarissa M. Maya-Monteiro ◽  
Patricia E. Almeida ◽  
Heloisa D'Ávila ◽  
Aline S. Martins ◽  
Ana Paula Rezende ◽  
...  
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Lipid Body ◽  
Target Of Rapamycin ◽  
Phosphatidylinositol 3 Kinase ◽  
Body Formation ◽  
Dependent Mechanism ◽  
Phosphatidylinositol 3

scholarly journals Regulation of Hepatic Insulin-Like Growth Factor-Binding Protein-1 Gene Expression by Insulin: Central Role for Mammalian Target of Rapamycin Independent of Forkhead Box O Proteins

Endocrinology ◽  
2006 ◽  
Vol 147 (5) ◽  
pp. 2383-2391 ◽  
Author(s):  
Catherine Mounier ◽  
Victor Dumas ◽  
Barry I. Posner
Keyword(s):  
Gene Expression ◽  
Rat Liver ◽  
Binding Protein ◽  
Mammalian Target Of Rapamycin ◽  
Pi3 Kinase ◽  
Target Of Rapamycin ◽  
Mrna Levels ◽  
Phosphatidylinositol 3 Kinase ◽  
Insulin Inhibition ◽  
Phosphatidylinositol 3

The expression of IGF-binding protein-1 (IGFBP-1) is induced in rat liver by dexamethasone and glucagon and is completely inhibited by 100 nm insulin. Various studies have implicated phosphatidylinositol 3-kinase, protein kinase B (Akt), phosphorylation of the transcription factors forkhead in rhabdomyosarcoma 1 (Foxo1)/Foxo3, and the mammalian target of rapamycin (mTOR) in insulin’s effect. In this study we examined insulin regulation of IGFBP-1 in both subconfluent and confluent hepatocytes. In subconfluent hepatocytes, insulin inhibition of IGFBP-1 mRNA levels was blocked by inhibiting PI3 kinase activation, and there was a corresponding inhibition of Foxo1/Foxo3 phosphorylation. In these same cells, inhibition of the insulin effect by rapamycin occurred in the presence of insulin-induced Foxo1/Foxo3 phosphorylation. In confluent hepatocytes, insulin could not activate the phosphatidylinositol 3-kinase (PI3 kinase)-Akt-Foxo1/Foxo3 pathway, but still inhibited IGFBP-1 gene expression in an mTOR-dependent manner. In subconfluent hepatocytes, the serine/threonine phosphatase inhibitor okadaic acid (100 nm) partially inhibited IGFBP-1 gene expression by 40%, but did not produce phosphorylation of either Akt or Foxo proteins. In contrast, 1 nm insulin inhibited the IGFBP-1 mRNA level by 40% and correspondingly activated Akt and Foxo1/Foxo3 phosphorylation to a level comparable to that observed with 100 nm insulin. These results suggest a potential role for a serine/threonine phosphatase(s) in the regulation of IGFBP-1 gene transcription, which is not downstream of mTOR and is independent of Akt. In conclusion, we have found that in rat liver, insulin inhibition of IGFBP-1 mRNA levels can occur in the absence of the phosphorylation of Foxo1/Foxo3, whereas activation of the mTOR pathway is both necessary and sufficient.

scholarly journals Role for Akt3/Protein Kinase Bγ in Attainment of Normal Brain Size

2005 ◽  
Vol 25 (5) ◽  
pp. 1869-1878 ◽  
Author(s):  
Rachael M. Easton ◽  
Han Cho ◽  
Kristin Roovers ◽  
Diana W. Shineman ◽  
Moshe Mizrahi ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Brain Size ◽  
Mammalian Target Of Rapamycin ◽  
Normal Growth ◽  
Cell Number ◽  
Normal Brain ◽  
Phosphatidylinositol 3 Kinase ◽  
Serine Threonine Kinase ◽  
Specific Regulation ◽  
Proportional Decrease

ABSTRACT Studies of Drosophila and mammals have revealed the importance of insulin signaling through phosphatidylinositol 3-kinase and the serine/threonine kinase Akt/protein kinase B for the regulation of cell, organ, and organismal growth. In mammals, three highly conserved proteins, Akt1, Akt2, and Akt3, comprise the Akt family, of which the first two are required for normal growth and metabolism, respectively. Here we address the function of Akt3. Like Akt1, Akt3 is not required for the maintenance of normal carbohydrate metabolism but is essential for the attainment of normal organ size. However, in contrast to Akt1 − / − mice, which display a proportional decrease in the sizes of all organs, Akt3 −/− mice present a selective 20% decrease in brain size. Moreover, although Akt1- and Akt3-deficient brains are reduced in size to approximately the same degree, the absence of Akt1 leads to a reduction in cell number, whereas the lack of Akt3 results in smaller and fewer cells. Finally, mammalian target of rapamycin signaling is attenuated in the brains of Akt3 −/− but not Akt1 −/− mice, suggesting that differential regulation of this pathway contributes to an isoform-specific regulation of cell growth.

scholarly journals De Novo Mutational Signature Discovery in Tumor Genomes using SparseSignatures

2018 ◽  
Author(s):  
Avantika Lal ◽  
Keli Liu ◽  
Robert Tibshirani ◽  
Arend Sidow ◽  
Daniele Ramazzotti
Keyword(s):  
Cross Validation ◽  
De Novo ◽  
State Of The Art ◽  
Point Mutations ◽  
Simulated Data ◽  
Large Datasets ◽  
Genome Sequences ◽  
Mutational Signatures ◽  
Mutational Signature ◽  
Current State

AbstractCancer is the result of mutagenic processes that can be inferred from tumor genomes by analyzing rate spectra of point mutations, or “mutational signatures”. Here we present SparseSignatures, a novel framework to extract signatures from somatic point mutation data. Our approach incorporates DNA replication error as a background, employs regularization to reduce noise in non-background signatures, uses cross-validation to identify the number of signatures, and is scalable to large datasets. We show that SparseSignatures outperforms current state-of-the-art methods on simulated data using standard metrics. We then apply SparseSignatures to whole genome sequences of 147 tumors from pancreatic cancer, discovering 8 signatures in addition to the background.

BRAF gene alterations and enhanced mammalian target of rapamycin signaling in gangliogliomas

2017 ◽  
Vol 65 (5) ◽  
pp. 1076 ◽  
Author(s):  
Chitra Sarkar ◽  
Aanchal Kakkar ◽  
Atreye Majumdar ◽  
Pankaj Pathak ◽  
Anupam Kumar ◽  
...  
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Braf Gene ◽  
Gene Alterations
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