scholarly journals Exquisite sensitivity of adrenocortical carcinomas to induction of ferroptosis

2019 ◽  
Vol 116 (44) ◽  
pp. 22269-22274 ◽  
Author(s):  
Alexia Belavgeni ◽  
Stefan R. Bornstein ◽  
Anne von Mässenhausen ◽  
Wulf Tonnus ◽  
Julian Stumpf ◽  
...  
Keyword(s):  
Direct Inhibition ◽  
Poor Survival ◽  
Membrane Blebbing ◽  
Regulated Necrosis ◽  
Fibrosarcoma Cells ◽  
Elevated Expression ◽  
H295r Cells ◽  
Ghrh Antagonists ◽  
Adrenocortical Carcinomas ◽  
Higher Sensitivity

Adrenocortical carcinomas (ACCs) are rare and highly malignant cancers associated with poor survival of patients. Currently, mitotane, a nonspecific derivative of the pesticide DDT (1,1-(dichlorobiphenyl)-2,2-dichloroethane), is used as the standard treatment, but its mechanism of action in ACCs remains elusive. Here we demonstrate that the human ACC NCI-H295R cell line is remarkably sensitive to induction of ferroptosis, while mitotane does not induce this iron-dependent mode of regulated necrosis. Supplementation with insulin, transferrin, and selenium (ITS) is commonly used to keep NCI-H295R cells in cell culture. We show that this supplementation prevents spontaneous ferroptosis, especially when it contains polyunsaturated fatty acids (PUFAs), such as linoleic acid. Inhibitors of apoptosis (zVAD, emricasan) do not prevent the mitotane-induced cell death but morphologically prevent membrane blebbing. The expression of glutathione peroxidase 4 (GPX4) in H295R cells, however, is significantly higher when compared to HT1080 fibrosarcoma cells, suggesting a role for ferroptosis. Direct inhibition of GPX4 in H295R cells led to high necrotic populations compared to control, while cotreatment with ferrostatin-1 (Fer-1) completely reverted ferroptosis. Interestingly, the analysis of public databases revealed that several key players of the ferroptosis pathway are hypermethylated and/or mutated in human ACCs. Finally, we also detected that growth hormone-releasing hormone (GHRH) antagonists, such as MIA602, kill H295R cells in a nonapoptotic manner. In summary, we found elevated expression of GPX4 and higher sensitivity to ferroptosis in ACCs. We hypothesize that instead of treatment with mitotane, human adrenocortical carcinomas may be much more sensitive to induction of ferroptosis.

scholarly journals Elevated Expression of miR-210 Predicts Poor Survival of Cancer Patients: A Systematic Review and Meta-Analysis

PLoS ONE ◽  
2014 ◽  
Vol 9 (2) ◽  
pp. e89223 ◽  
Author(s):  
Jian Wang ◽  
Jiqing Zhao ◽  
Mengjing Shi ◽  
Yu Ding ◽  
Huiqin Sun ◽  
...  
Keyword(s):  
Systematic Review ◽  
Cancer Patients ◽  
Meta Analysis ◽  
Poor Survival ◽  
Elevated Expression

scholarly journals Time-resolved ultrastructure of the cortical actin cytoskeleton in dynamic membrane blebs

2018 ◽  
Vol 218 (2) ◽  
pp. 445-454 ◽  
Author(s):  
Aleksandra S. Chikina ◽  
Tatyana M. Svitkina ◽  
Antonina Y. Alexandrova
Keyword(s):  
Cortical Actin ◽  
Dynamic Membrane ◽  
Time Resolved ◽  
Membrane Blebbing ◽  
Cytoskeleton Organization ◽  
Cellular Processes ◽  
Actin Cortex ◽  
Fibrosarcoma Cells ◽  
Structural Mechanisms ◽  
Intracellular Pressure

Membrane blebbing accompanies various cellular processes, including cytokinesis, apoptosis, and cell migration, especially invasive migration of cancer cells. Blebs are extruded by intracellular pressure and are initially cytoskeleton-free, but they subsequently assemble the cytoskeleton, which can drive bleb retraction. Despite increasing appreciation of physiological significance of blebbing, the molecular and, especially, structural mechanisms controlling bleb dynamics are incompletely understood. We induced membrane blebbing in human HT1080 fibrosarcoma cells by inhibiting the Arp2/3 complex. Using correlative platinum replica electron microscopy, we characterize cytoskeletal architecture of the actin cortex in cells during initiation of blebbing and in blebs at different stages of their expansion–retraction cycle. The transition to blebbing in these conditions occurred through an intermediate filopodial stage, whereas bleb initiation was biased toward filopodial bases, where the cytoskeleton exhibited local weaknesses. Different stages of the bleb life cycle (expansion, pausing, and retraction) are characterized by specific features of cytoskeleton organization that provide implications about mechanisms of cytoskeleton assembly and bleb retraction.

Elevated expression of HMGB1 is prognostic of poor survival in patients with relapsed/refractory T/NK-CL

2021 ◽  
Author(s):  
Caiqin Wang ◽  
Yu Wang ◽  
Jianghua Cao ◽  
Xiaoqing Sun ◽  
Xiaohua He ◽  
...  
Keyword(s):  
Poor Survival ◽  
Elevated Expression

scholarly journals Integrated genomics and comprehensive validation reveal drivers of genomic evolution in esophageal adenocarcinoma

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Subodh Kumar ◽  
Leutz Buon ◽  
Srikanth Talluri ◽  
Marco Roncador ◽  
Chengcheng Liao ◽  
...  
Keyword(s):  
Genomic Instability ◽  
Esophageal Adenocarcinoma ◽  
Whole Genome ◽  
Genomic Evolution ◽  
Poor Survival ◽  
Mutational Signatures ◽  
Functional Studies ◽  
Development Of Resistance ◽  
Elevated Expression ◽  
Integrated Genomics

AbstractEsophageal adenocarcinoma (EAC) is associated with a marked genomic instability, which underlies disease progression and development of resistance to treatment. In this study, we used an integrated genomics approach to identify a genomic instability signature. Here we show that elevated expression of this signature correlates with poor survival in EAC as well as three other cancers. Knockout and overexpression screens establish the relevance of these genes to genomic instability. Indepth evaluation of three genes (TTK, TPX2 and RAD54B) confirms their role in genomic instability and tumor growth. Mutational signatures identified by whole genome sequencing and functional studies demonstrate that DNA damage and homologous recombination are common mechanisms of genomic instability induced by these genes. Our data suggest that the inhibitors of TTK and possibly other genes identified in this study have potential to inhibit/reduce growth and spontaneous as well as chemotherapy-induced genomic instability in EAC and possibly other cancers.

scholarly journals Elevated FBXO45 promotes liver tumorigenesis through enhancing IGF2BP1 ubiquitination and subsequent PLK1 upregulation

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Xiao-Tong Lin ◽  
Hong-Qiang Yu ◽  
Lei Fang ◽  
Ye Tan ◽  
Ze-Yu Liu ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Positive Association ◽  
Poor Survival ◽  
Tissue Samples ◽  
New Strategy ◽  
Elevated Expression ◽  
Subsequent Activation ◽  
Plk1 Expression

Dysregulation of tumor-relevant proteins may contribute to human hepatocellular carcinoma (HCC) tumorigenesis. FBXO45 is an E3 ubiquitin ligase that is frequently elevated expression in human HCC. However, it remains unknown whether FBXO45 is associated with hepatocarcinogenesis and how to treat HCC patients with high FBXO45 expression. Here, IHC and qPCR analysis revealed that FBXO45 protein and mRNA were highly expressed in 54.3% (57 of 105) and 52.2% (132 of 253) of the HCC tissue samples, respectively. Highly expressed FBXO45 promoted liver tumorigenesis in transgenic mice. Mechanistically, FBXO45 promoted IGF2BP1 ubiquitination at the Lys190 and Lys450 sites and subsequent activation, leading to the upregulation of PLK1 expression and the induction of cell proliferation and liver tumorigenesis in vitro and in vivo. PLK1 inhibition or IGF2BP1 knockdown significantly blocked FBXO45-driven liver tumorigenesis in FBXO45 transgenic mice, primary cells and HCCs. Furthermore, IHC analysis on HCC tissue samples revealed a positive association between the hyperexpression of FBXO45 and PLK1/IGF2BP1, and both had positive relationship with poor survival in HCC patients. Thus, FBXO45 plays an important role in promoting liver tumorigenesis through IGF2BP1 ubiquitination and activation, and subsequent PLK1 upregulation, suggesting a new strategy for treating HCC by targeting FBXO45/IGF2BP1/PLK1 axis.

scholarly journals LncRNA TUG1 contributes to the tumorigenesis of lung adenocarcinoma by regulating miR-138-5p-HIF1A axis

2021 ◽  
Vol 35 ◽  
pp. 205873842110482
Author(s):  
Ke Li ◽  
Huatao Niu ◽  
Ying Wang ◽  
Ruilei Li ◽  
Yuan Zhao ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Lung Adenocarcinoma ◽  
Luciferase Gene ◽  
Loss Of Function ◽  
Poor Survival ◽  
Elevated Expression ◽  
The Relationship ◽  
Lncrna Tug1

Introduction: Increasing evidence indicates that lncRNA TUG1 represents an oncogenic factor in cancer. But, the mechanisms by which lncRNA TUG1 contributes to lung adenocarcinoma (LAC) remain undocumented. Methods: The relationship between lncRNA TUG1/miR-138-5p expression and clinical outcomes in patients with LAC was indicated by qPCR, FISH, and TCGA cohort. Gain- or loss-of-function experiments and in vivo tumorigenesis were used to assess the role of lncRNA TUG1 in LAC. The interplay between TUG1 and miR-138-5p was validated by luciferase gene report and RIP assays. qPCR and Western blot analyses were used to investigate the effects of TUG1 on miR-138-5p/HIF1A axis in LAC cells. Results: We found that upregulation of TUG1 or downregulation of miR-138-5p was associated with lymph node or distant metastasis and indicated a poor survival in LAC. Reduced expression of TUG1 restrained the growth of LAC cells, while restored expression of TUG1 had the opposite effects. TUG1 was identified to negatively regulate miR-138-5p expression, and miR-138-5p reversed TUG1-induced cell proliferation by targeting HIF1A. Elevated expression of HIF1A predicted a poor survival in LAC. Conclusion: Our findings demonstrate that lncRNA TUG1 promotes the growth of LAC by regulating miR-138-5p-HIF1A axis.

Sign in / Sign up

Export Citation Format

Share Document